|
Inhibition measurement of orotate formation from radiolabeled dihydroorotate, using partially purified DHODase isolated from human liver.
|
None
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Immunosuppressive structure-activity relationships of Brequinar and related cinchoninic acid derivatives
Year : 1995
Volume : 5
Issue : 14
First Page : 1549
Last Page : 1554
Authors : Batt DG, Copeland RA, Dowling RL, Gardner TL, Jones EA, Orwat MJ, Pinto DJ, Pitts WJ, Magolda RL, Jaffee BD
|
Ability to inhibit proliferation in human lymphocytes by mixed lymphocyte reaction (MLR)
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Immunosuppressive structure-activity relationships of Brequinar and related cinchoninic acid derivatives
Year : 1995
Volume : 5
Issue : 14
First Page : 1549
Last Page : 1554
Authors : Batt DG, Copeland RA, Dowling RL, Gardner TL, Jones EA, Orwat MJ, Pinto DJ, Pitts WJ, Magolda RL, Jaffee BD
|
Inhibitory activity against recombinant human DHODH
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Biphenyl-4-ylcarbamoyl thiophene carboxylic acids as potent DHODH inhibitors.
Year : 2006
Volume : 16
Issue : 2
First Page : 267
Last Page : 270
Authors : Leban J, Kralik M, Mies J, Baumgartner R, Gassen M, Tasler S.
Abstract : A previously discovered DHODH inhibitor series was further improved by replacing the cyclopentene ring by aromatic heterocycles. Different isomers of these compounds were prepared by the directed ortho-metallation procedure. The compounds are more active than the corresponding cyclopentene analogs and show potent effects on PBMC's proliferation.
|
Inhibition of recombinant human DHODH by using blue indicator dye DCIP
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures.
Year : 2010
Volume : 20
Issue : 6
First Page : 1981
Last Page : 1984
Authors : McLean LR, Zhang Y, Degnen W, Peppard J, Cabel D, Zou C, Tsay JT, Subramaniam A, Vaz RJ, Li Y.
Abstract : Amino-benzoic acid derivatives 1-4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.
|
Inhibition of dihydroorotate dehydrogenase in Wistar rat liver mitochondrial/microsomal membranes measured for 5 mins by 2,6-dichlorophenolindophenol reduction-based spectrophotometry
|
Rattus norvegicus
|
33.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : New inhibitors of dihydroorotate dehydrogenase (DHODH) based on the 4-hydroxy-1,2,5-oxadiazol-3-yl (hydroxyfurazanyl) scaffold.
Year : 2012
Volume : 49
First Page : 102
Last Page : 109
Authors : Lolli ML, Giorgis M, Tosco P, Foti A, Fruttero R, Gasco A.
Abstract : Based on some structural analogies with leflunomide and brequinar, two well-known inhibitors of dihydroorotate dehydrogenase (DHODH), a new series of products was designed, by joining the substituted biphenyl moiety to the 4-hydroxy-1,2,5-oxadiazol-3-yl scaffold through an amide bridge. The compounds were studied for their DHODH inhibitory activity on rat liver mitochondrial/microsomal membranes. The activity was found to be closely dependent on the substitution pattern at the biphenyl system; the most potent products were those bearing two or four fluorine atoms at the phenyl adjacent to the oxadiazole ring. A molecular modeling study suggested that these structures might have a brequinar-like binding mode. The greater potency of fluorinated analogs may depend partly on enhanced interactions with the hydrophobic ubiquinone channel, and partly on the role of fluorine in stabilizing the putative bioactive conformation.
|
Inhibition of rat recombinant His-tagged truncated DHODH expressed in Escherichia coli using dihydroorotate as substrate by chromogen reduction assay
|
Rattus norvegicus
|
127.0
nM
|
|
Journal : J. Med. Chem.
Title : On dihydroorotate dehydrogenases and their inhibitors and uses.
Year : 2013
Volume : 56
Issue : 8
First Page : 3148
Last Page : 3167
Authors : Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL.
Abstract : Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.
|
Inhibition of human DHODH
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : On dihydroorotate dehydrogenases and their inhibitors and uses.
Year : 2013
Volume : 56
Issue : 8
First Page : 3148
Last Page : 3167
Authors : Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL.
Abstract : Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.
|
Inhibition of rat purified recombinant DHODH
|
Rattus norvegicus
|
367.0
nM
|
|
Journal : J. Med. Chem.
Title : On dihydroorotate dehydrogenases and their inhibitors and uses.
Year : 2013
Volume : 56
Issue : 8
First Page : 3148
Last Page : 3167
Authors : Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL.
Abstract : Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.
|
Inhibition of human purified recombinant DHODH
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : On dihydroorotate dehydrogenases and their inhibitors and uses.
Year : 2013
Volume : 56
Issue : 8
First Page : 3148
Last Page : 3167
Authors : Munier-Lehmann H, Vidalain PO, Tangy F, Janin YL.
Abstract : Proper nucleosides availability is crucial for the proliferation of living entities (eukaryotic cells, parasites, bacteria, and virus). Accordingly, the uses of inhibitors of the de novo nucleosides biosynthetic pathways have been investigated in the past. In the following we have focused on dihydroorotate dehydrogenase (DHODH), the fourth enzyme in the de novo pyrimidine nucleosides biosynthetic pathway. We first described the different types of enzyme in terms of sequence, structure, and biochemistry, including the reported bioassays. In a second part, the series of inhibitors of this enzyme along with a description of their potential or actual uses were reviewed. These inhibitors are indeed used in medicine to treat autoimmune diseases such as rheumatoid arthritis or multiple sclerosis (leflunomide and teriflunomide) and have been investigated in treatments of cancer, virus, and parasite infections (i.e., malaria) as well as in crop science.
|
Antiviral activity against influenza A virus A/WSN/33 (H0N1) infected in MDCK cells after 48 hrs by plaque assay
|
Influenza A virus
|
460.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.
Year : 2013
Volume : 4
Issue : 6
First Page : 517
Last Page : 521
Authors : Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK.
Abstract : It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.
|
Inhibition of human DHODH
|
Homo sapiens
|
12.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.
Year : 2013
Volume : 4
Issue : 6
First Page : 517
Last Page : 521
Authors : Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK.
Abstract : It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.
|
Antiviral activity against VSV infected in MDCK cells assessed as inhibition of VSV replication after 48 hrs by plaque assay
|
Vesicular stomatitis virus
|
300.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : SAR Based Optimization of a 4-Quinoline Carboxylic Acid Analog with Potent Anti-Viral Activity.
Year : 2013
Volume : 4
Issue : 6
First Page : 517
Last Page : 521
Authors : Das P, Deng X, Zhang L, Roth MG, Fontoura BM, Phillips MA, De Brabander JK.
Abstract : It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.
|
Inhibition of His-tagged human DHODH assessed as reduction of DCIP by spectrophotometry
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH).
Year : 2015
Volume : 58
Issue : 2
First Page : 860
Last Page : 877
Authors : Munier-Lehmann H, Lucas-Hourani M, Guillou S, Helynck O, Zanghi G, Noel A, Tangy F, Vidalain PO, Janin YL.
Abstract : From a research program aimed at the design of new chemical entities followed by extensive screening on various models of infectious diseases, an original series of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidines endowed with notable antiviral properties were found. Using a whole cell measles virus replication assay, we describe here some aspects of the iterative process that, from 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyrimidine, led to 2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine and a 4000-fold improvement of antiviral activity with a subnanomolar level of inhibition. Moreover, recent precedents in the literature describing antiviral derivatives acting at the level of the de novo pyrimidine biosynthetic pathway led us to determine that the mode of action of this series is based on the inhibition of the cellular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this pathway. Biochemical studies with recombinant human DHODH led us to measure IC50 as low as 13 nM for the best example of this original series when using 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone (coenzyme Q1) as a surrogate for coenzyme Q10, the cofactor of this enzyme.
|
Inhibition of human recombinant DHODH
|
Homo sapiens
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).
Year : 2015
Volume : 58
Issue : 14
First Page : 5579
Last Page : 5598
Authors : Lucas-Hourani M, Munier-Lehmann H, El Mazouni F, Malmquist NA, Harpon J, Coutant EP, Guillou S, Helynck O, Noel A, Scherf A, Phillips MA, Tangy F, Vidalain PO, Janin YL.
Abstract : Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure-activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
|
Inhibition of cell proliferation of human Jurkat cells incubated for 72 hrs by Celltiter-Glo assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : J. Med. Chem.
Title : Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).
Year : 2015
Volume : 58
Issue : 14
First Page : 5579
Last Page : 5598
Authors : Lucas-Hourani M, Munier-Lehmann H, El Mazouni F, Malmquist NA, Harpon J, Coutant EP, Guillou S, Helynck O, Noel A, Scherf A, Phillips MA, Tangy F, Vidalain PO, Janin YL.
Abstract : Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure-activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.
|
Inhibition of DHODH (unknown origin) using L-DHO, DUQ, DCIP as substrate preincubated for 30 mins followed by substrate addition measured after 20 mins by multilabel plate reader analysis
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH.
Year : 2015
Volume : 23
Issue : 15
First Page : 4669
Last Page : 4680
Authors : Abdullah I, Chee CF, Lee YK, Thunuguntla SS, Satish Reddy K, Nellore K, Antony T, Verma J, Mun KW, Othman S, Subramanya H, Rahman NA.
Abstract : Poly (ADP-ribose) polymerases (PARPs) play diverse roles in various cellular processes that involve DNA repair and programmed cell death. Amongst these polymerases is PARP-1 which is the key DNA damage-sensing enzyme that acts as an initiator for the DNA repair mechanism. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the pyrimidine biosynthetic pathway which is an important target for anti-hyperproliferative and anti-inflammatory drug design. Since these enzymes share a common role in the DNA replication and repair mechanisms, it may be beneficial to target both PARP-1 and DHODH in attempts to design new anti-cancer agents. Benzimidazole derivatives have shown a wide variety of pharmacological activities including PARP and DHODH inhibition. We hereby report the design, synthesis and bioactivities of a series of benzimidazole derivatives as inhibitors of both the PARP-1 and DHODH enzymes.
|
Inhibition of N-terminally truncated human DHODH (Met30 to Arg396 residues) expressed in Escherichia coli BL21 (DE3) using dihydroorotate as substrate preincubated for 5 mins followed by substrate addition measured every 30 secs for 6 mins by DCIP-based spectrophotometric assay
|
Homo sapiens
|
7.4
nM
|
|
Journal : MedChemComm
Title : Biological evaluation of quinoline derivatives as inhibitors of human dihydroorotate dehydrogenase
Year : 2016
Volume : 7
Issue : 5
First Page : 853
Last Page : 858
Authors : Wang J, Diao Y, Zhu J, Li S, Zhao Z, Li H, Zhu L
|
Induction of bone marrow cell differentiation isolated from ER-HOXA9 fusion protein expressed mouse harboring GFP-lysozyme assessed as upregulation of CD11b/MAC1 after 4 days by flow cytometry
|
Mus musculus
|
510.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Year : 2016
Volume : 7
Issue : 12
First Page : 1112
Last Page : 1117
Authors : Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL.
Abstract : Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.
|
Induction of human U937 cell differentiation after 4 days by flow cytometry
|
Homo sapiens
|
44.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Year : 2016
Volume : 7
Issue : 12
First Page : 1112
Last Page : 1117
Authors : Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL.
Abstract : Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.
|
Induction of human THP1 cell differentiation after 4 days by flow cytometry
|
Homo sapiens
|
94.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Year : 2016
Volume : 7
Issue : 12
First Page : 1112
Last Page : 1117
Authors : Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL.
Abstract : Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.
|
Inhibition of human recombinant DHODH
|
Homo sapiens
|
4.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Year : 2016
Volume : 7
Issue : 12
First Page : 1112
Last Page : 1117
Authors : Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL.
Abstract : Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.
|
Inhibition of human recombinant DHODH expressed in baculovirus infected insect cells using dihydroorotate as substrate in presence of quinone by dichlorophenol-indophenol dye based assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.
Year : 2016
Volume : 7
Issue : 12
First Page : 1112
Last Page : 1117
Authors : Lewis TA, Sykes DB, Law JM, Muñoz B, Rustiguel JK, Nonato MC, Scadden DT, Schreiber SL.
Abstract : Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.
|
Inhibition of recombinant human N-terminal truncated GST-tagged DHFR (31 to 395 residues) expressed in Escherichia coli BL21(DE3) pyrD using DHO as substrate preincubated for 5 mins followed by substrate addition measured for 5 mins by DCIP oxidation based CoQ10 enzyme coupled assay
|
Homo sapiens
|
1.8
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.
Year : 2017
Volume : 129
First Page : 287
Last Page : 302
Authors : Sainas S, Pippione AC, Giorgis M, Lupino E, Goyal P, Ramondetti C, Buccinnà B, Piccinini M, Braga RC, Andrade CH, Andersson M, Moritzer AC, Friemann R, Mensa S, Al-Kadaraghi S, Boschi D, Lolli ML.
Abstract : A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.
|
Antiproliferative activity against human Jurkat T cells assessed as DNA content after 72 hrs by Hoechst 33258 dye based fluorometric method
|
Homo sapiens
|
930.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and X-ray structural studies of potent human dihydroorotate dehydrogenase inhibitors based on hydroxylated azole scaffolds.
Year : 2017
Volume : 129
First Page : 287
Last Page : 302
Authors : Sainas S, Pippione AC, Giorgis M, Lupino E, Goyal P, Ramondetti C, Buccinnà B, Piccinini M, Braga RC, Andrade CH, Andersson M, Moritzer AC, Friemann R, Mensa S, Al-Kadaraghi S, Boschi D, Lolli ML.
Abstract : A new generation of potent hDHODH inhibitors designed by a scaffold-hopping replacement of the quinolinecarboxylate moiety of brequinar, one of the most potent known hDHODH inhibitors, is presented here. Their general structure is characterized by a biphenyl moiety joined through an amide bridge with an acidic hydroxyazole scaffold (hydroxylated thiadiazole, pyrazole and triazole). Molecular modelling suggested that these structures should adopt a brequinar-like binding mode involving interactions with subsites 1, 2 and 4 of the hDHODH binding site. Initially, the inhibitory activity of the compounds was studied on recombinant hDHODH. The most potent compound of the series in the enzymatic assays was the thiadiazole analogue 4 (IC50 16 nM). The activity was found to be dependent on the fluoro substitution pattern at the biphenyl moiety as well as on the choice/substitution of the heterocyclic ring. Structure determination of hDHODH co-crystallized with one representative compound from each series (4, 5 and 6) confirmed the brequinar-like binding mode as suggested by modelling. The specificity of the observed effects of the compound series was tested in cell-based assays for antiproliferation activity using Jurkat cells and PHA-stimulated PBMC. These tests were also verified by addition of exogenous uridine to the culture medium. In particular, the triazole analogue 6 (IC50 against hDHODH: 45 nM) exerted potent in vitro antiproliferative and immunosuppressive activity without affecting cell survival.
|
Inhibition of recombinant N-terminal GST-tagged human DHODH (31 to 395 residues) expressed in Escherichia coli BL21(DE3) assessed as inhibition of DCIP reduction using dihydroorotate as substrate preincubated for 5 mins followed by substrate addition measured after 5 mins
|
Homo sapiens
|
1.8
nM
|
|
Journal : J Med Chem
Title : Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.
Year : 2018
Volume : 61
Issue : 14
First Page : 6034
Last Page : 6055
Authors : Sainas S, Pippione AC, Lupino E, Giorgis M, Circosta P, Gaidano V, Goyal P, Bonanni D, Rolando B, Cignetti A, Ducime A, Andersson M, Järvå M, Friemann R, Piccinini M, Ramondetti C, Buccinnà B, Al-Karadaghi S, Boschi D, Saglio G, Lolli ML.
Abstract : Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
|
Antiproliferative activity against human Jurkat T cells assessed as DNA content after 72 hrs by Hoechst 33258 dye-based fluorescence assay
|
Homo sapiens
|
910.0
nM
|
|
Journal : J Med Chem
Title : Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.
Year : 2018
Volume : 61
Issue : 14
First Page : 6034
Last Page : 6055
Authors : Sainas S, Pippione AC, Lupino E, Giorgis M, Circosta P, Gaidano V, Goyal P, Bonanni D, Rolando B, Cignetti A, Ducime A, Andersson M, Järvå M, Friemann R, Piccinini M, Ramondetti C, Buccinnà B, Al-Karadaghi S, Boschi D, Saglio G, Lolli ML.
Abstract : Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.
|
Inhibition of DHODH (unknown origin) expressed in Escherichia coli Rosetta2(DE3) assessed as reduction of DCIP using dihydroorotate as substrate preincubated for 30 mins followed by substrate addition in presence of CoQ10 measured after 1 hr
|
Homo sapiens
|
7.3
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.
Year : 2018
Volume : 61
Issue : 12
First Page : 5162
Last Page : 5186
Authors : Madak JT, Cuthbertson CR, Miyata Y, Tamura S, Petrunak EM, Stuckey JA, Han Y, He M, Sun D, Showalter HD, Neamati N.
Abstract : We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.
|
Antiproliferative activity against human HCT116 cells over-expressing DHODH after 72 hrs by MTT assay
|
Homo sapiens
|
679.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.
Year : 2018
Volume : 61
Issue : 12
First Page : 5162
Last Page : 5186
Authors : Madak JT, Cuthbertson CR, Miyata Y, Tamura S, Petrunak EM, Stuckey JA, Han Y, He M, Sun D, Showalter HD, Neamati N.
Abstract : We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.
|
Antiproliferative activity against human HL60 cells after 72 hrs by MTT assay
|
Homo sapiens
|
544.0
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase.
Year : 2018
Volume : 61
Issue : 12
First Page : 5162
Last Page : 5186
Authors : Madak JT, Cuthbertson CR, Miyata Y, Tamura S, Petrunak EM, Stuckey JA, Han Y, He M, Sun D, Showalter HD, Neamati N.
Abstract : We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability ( F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.
|
Inhibition of human DHODH using dihydroorotate substrate by DCIP assay
|
Homo sapiens
|
8.4
nM
|
|
Journal : MedChemComm
Title : Synthesis, structure-activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase.
Year : 2017
Volume : 8
Issue : 6
First Page : 1297
Last Page : 1302
Authors : Zeng F, Qi T, Li C, Li T, Li H, Li S, Zhu L, Xu X.
Abstract : A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (<i>h</i>DHODH) inhibitors. Compounds <b>26</b> and <b>31</b> displayed IC<sub>50</sub> values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound <b>31</b> could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the <i>para</i>- or <i>meta</i>-position of the phenyl group at R will lead to the identification of more potent <i>h</i>DHODH inhibitors.
|
Inhibition of human DHODH using DHO as substrate measured at 4 secs interval for 60 secs by DCIP reduction based indirect assay
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur J Med Chem
Title : Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase.
Year : 2019
Volume : 167
First Page : 357
Last Page : 366
Authors : Calil FA, David JS, Chiappetta ERC, Fumagalli F, Mello RB, Leite FHA, Castilho MS, Emery FS, Nonato MC.
Abstract : Schistosomiasis ranks second only to malaria as the most common parasitic disease worldwide. 700 million people are at risk and 240 million are already infected. Praziquantel is the anthelmintic of choice but decreasing efficacy has already been documented. In this work, we exploited the inhibition of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH) as a strategy to develop new therapeutics to fight schistosomiasis. A series of quinones (atovaquone derivatives and precursors) was evaluated regarding potency and selectivity against both SmDHODH and human DHODH. The best compound identified is 17 (2-hydroxy-3-isopentylnaphthalene-1,4-dione) with IC<sub>50</sub> = 23 ± 4 nM and selectivity index of 30.83. Some of the new compounds are useful pharmacological tools and represent new lead structures for further optimization.
|
Antiviral activity against Yellow fever virus infected in human A549 cells assessed as reduction in virus replication
|
Yellow fever virus
|
78.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
Antiviral activity against West Nile virus infected in human A549 cells assessed as reduction in virus replication
|
West Nile virus
|
78.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
Antiviral activity against Dengue virus infected in human A549 cells assessed as reduction in virus replication
|
Dengue virus
|
78.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
Antiviral activity against Western equine encephalomyelitis virus infected in human A549 cells assessed as reduction in virus replication
|
Western equine encephalomyelitis virus
|
78.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
Antiviral activity against Vesicular stomatitis virus infected in human A549 cells assessed as reduction in virus replication
|
Vesicular stomatitis virus
|
78.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
Inhibition of human DHODH
|
Homo sapiens
|
37.0
nM
|
|
Journal : Eur J Med Chem
Title : Dihydroorotate dehydrogenase inhibitors in anti-infective drug research.
Year : 2019
Volume : 183
First Page : 111681
Last Page : 111681
Authors : Boschi D, Pippione AC, Sainas S, Lolli ML.
Abstract : Pyrimidines are essential for the cell survival and proliferation of living parasitic organisms, such as Helicobacter pylori, Plasmodium falciparum and Schistosoma mansoni, that are able to impact upon human health. Pyrimidine building blocks, in human cells, are synthesised via both de novo biosynthesis and salvage pathways, the latter of which is an effective way of recycling pre-existing nucleotides. As many parasitic organisms lack pyrimidine salvage pathways for pyrimidine nucleotides, blocking de novo biosynthesis is seen as an effective therapeutic means to selectively target the parasite without effecting the human host. Dihydroorotate dehydrogenase (DHODH), which is involved in the de novo biosynthesis of pyrimidines, is a validated target for anti-infective drug research. Recent advances in the DHODH microorganism field are discussed herein, as is the potential for the development of DHODH-targeted therapeutics.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.4
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
6.33
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
6.33
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Antiproliferative activity against human ARN8 cells assessed as reduction in cell viability incubated for 72 hrs by SRB assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : J Med Chem
Title : Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability.
Year : 2020
Volume : 63
Issue : 8
First Page : 3915
Last Page : 3934
Authors : Popova G, Ladds MJGW, Johansson L, Saleh A, Larsson J, Sandberg L, Sahlberg SH, Qian W, Gullberg H, Garg N, Gustavsson AL, Haraldsson M, Lane D, Yngve U, Lain S.
Abstract : Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound <b>51</b> as a favorable candidate for preclinical efficacy studies.
|
Inhibition of human DHODH using dihydroorotate as substrate and CoQ10 as co-substrate preincubated for 30 mins followed by substrate addition by DCIP coupled microplate reader assay
|
Homo sapiens
|
5.2
nM
|
|
Journal : J Med Chem
Title : Bifunctional Naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.
Year : 2020
Volume : 63
Issue : 14
First Page : 7633
Last Page : 7652
Authors : Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y.
Abstract : Human dihydroorotate dehydrogenase (<i>h</i>DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound <b>3s</b> with a naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against <i>h</i>DHODH. Further optimization led to compounds <b>11k</b> and <b>11l</b>, which inhibited <i>h</i>DHODH activity with IC<sub>50</sub> values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of <b>11k</b> and <b>11l</b> with <i>h</i>DHODH. Compounds <b>11k</b> and <b>11l</b> significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound <b>11l</b> displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound <b>11l</b> with <i>h</i>DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
|
Antiproliferative activity against human A375 cells assessed as reduction in cell viability measured after 48 hrs by MTT assay
|
Homo sapiens
|
590.0
nM
|
|
Journal : J Med Chem
Title : Bifunctional Naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.
Year : 2020
Volume : 63
Issue : 14
First Page : 7633
Last Page : 7652
Authors : Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y.
Abstract : Human dihydroorotate dehydrogenase (<i>h</i>DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound <b>3s</b> with a naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against <i>h</i>DHODH. Further optimization led to compounds <b>11k</b> and <b>11l</b>, which inhibited <i>h</i>DHODH activity with IC<sub>50</sub> values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of <b>11k</b> and <b>11l</b> with <i>h</i>DHODH. Compounds <b>11k</b> and <b>11l</b> significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound <b>11l</b> displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound <b>11l</b> with <i>h</i>DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
|
Antiproliferative activity against human K562 cells assessed as reduction in cell viability measured after 48 hrs by MTT assay
|
Homo sapiens
|
540.0
nM
|
|
Journal : J Med Chem
Title : Bifunctional Naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.
Year : 2020
Volume : 63
Issue : 14
First Page : 7633
Last Page : 7652
Authors : Zuo Z, Liu X, Qian X, Zeng T, Sang N, Liu H, Zhou Y, Tao L, Zhou X, Su N, Yu Y, Chen Q, Luo Y, Zhao Y.
Abstract : Human dihydroorotate dehydrogenase (<i>h</i>DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound <b>3s</b> with a naphtho[2,3-<i>d</i>][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against <i>h</i>DHODH. Further optimization led to compounds <b>11k</b> and <b>11l</b>, which inhibited <i>h</i>DHODH activity with IC<sub>50</sub> values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of <b>11k</b> and <b>11l</b> with <i>h</i>DHODH. Compounds <b>11k</b> and <b>11l</b> significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound <b>11l</b> displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound <b>11l</b> with <i>h</i>DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
|
Inhibition of human DHODH
|
Homo sapiens
|
0.48
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.
Year : 2020
Volume : 30
Issue : 22
First Page : 127589
Last Page : 127589
Authors : DeRatt LG,Christine Pietsch E,Tanner A,Shaffer P,Jacoby E,Wang W,Kazmi F,Zhang X,Attar RM,Edwards JP,Kuduk SD
Abstract : Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
|
Antiproliferative activity against human MOLM-13 cells
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : A carboxylic acid isostere screen of the DHODH inhibitor Brequinar.
Year : 2020
Volume : 30
Issue : 22
First Page : 127589
Last Page : 127589
Authors : DeRatt LG,Christine Pietsch E,Tanner A,Shaffer P,Jacoby E,Wang W,Kazmi F,Zhang X,Attar RM,Edwards JP,Kuduk SD
Abstract : Dihydroorotate dehydrogenase (DHODH) enzymatic activity impacts many aspects critical to cell proliferation and survival. Recently, DHODH has been identified as a target for acute myeloid differentiation therapy. In preclinical models of AML, the DHODH inhibitor Brequinar (BRQ) demonstrated potent anti-leukemic activity. Herein we describe a carboxylic acid isostere study of Brequinar which revealed a more potent non-carboxylic acid derivative with improved cellular potency and good pharmacokinetic properties.
|
Antiproliferative activity against human HT-29 cells assessed as cell growth inhibition measured after 48 hrs by SRB assay
|
Homo sapiens
|
371.54
nM
|
|
Antiproliferative activity against human HT-29 cells assessed as cell growth inhibition measured after 48 hrs by SRB assay
|
Homo sapiens
|
590.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human M21 cells assessed as cell growth inhibition measured after 48 hrs by SRB assay
|
Homo sapiens
|
570.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Inhibition of recombinant N-terminal His-tagged human DHODH (31 to 395 residues) expressed in Escherichia coli using L-DHO as substrate measured every 10 mins for 90 mins in presence of decylubiquinone by DCIP based colorimetric assay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human HT-1080 cells assessed as cell growth inhibition measured after 48 hrs by SRB assay
|
Homo sapiens
|
210.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human MCF7 cells assessed as cell growth inhibition measured after 48 hrs by SRB assay
|
Homo sapiens
|
269.15
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human CCRF-CEM cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
281.84
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human K562 cells assessed as cell growth inhibition incubated for 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
144.54
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human MOLT-4 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
89.13
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human RPMI-8226 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
371.54
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human SR cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
426.58
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human A549/ATCC cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
234.42
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human NCI-H460 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
128.82
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human COLO 205 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
512.86
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human HCT-116 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
87.1
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human HCT-15 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
56.23
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human KM12 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
208.93
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human SW-620 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
380.19
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human 786-0 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
194.98
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human ACHN cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
151.36
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human CAKI-1 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
912.01
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human SF-268 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
371.54
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human SF-295 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
239.88
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human SF-539 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
346.74
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human U-251 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
194.98
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human LOX IMVI cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
93.33
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human MDA-MB-435 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
371.54
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human UACC-62 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
263.03
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human IGROV-1 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
302.0
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human OVCAR-8 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
323.59
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human PC-3 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
758.58
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Antiproliferative activity against human DU-145 cells assessed as cell growth inhibition measured after 48 hrs by sulforhodamine B assay
|
Homo sapiens
|
263.03
nM
|
|
Journal : Bioorg Med Chem
Title : N-phenyl ureidobenzenesulfonates, a novel class of promising human dihydroorotate dehydrogenase inhibitors.
Year : 2020
Volume : 28
Issue : 22.0
First Page : 115739
Last Page : 115739
Authors : Bouzriba C,Larcher L,Gagné-Boulet M,Fortin S
Abstract : N-phenyl ureidobenzenesulfonates (PUB-SOs) is a new class of promising anticancer agents inducing replication stresses and cell cycle arrest in S-phase. However, the pharmacological target of PUB-SOs was still unidentified. Consequently, the objective of the present study was to identify and confirm the pharmacological target of the prototypical PUB-SO named 2-ethylphenyl 4-(3-ethylureido)benzenesulfonate (SFOM-0046) leading to the cell cycle arrest in S-phase. The antiproliferative and the cytotoxic activities of SFOM-0046 were characterized using the NCI-60 screening program and its fingerprint was analyzed by COMPARE algorithm. Then, human dihydroorotate dehydrogenase (hDHODH) colorimetric assay, uridine rescuing cell proliferation and molecular docking in the brequinar-binding site were performed. As a result, SFOM-0046 exhibited a mean antiproliferative activity of 3.5 μM in the NCI-60 screening program and evidenced that leukemia and colon cancer cell panels were more sensitive to SFOM-0046. COMPARE algorithm showed that the SFOM-0046 cytotoxic profile is equivalent to the ones of brequinar and dichloroallyl lawsone, two inhibitors of hDHODH. SFOM-0046 inhibited the hDHODH in the low nanomolar range (IC = 72 nM) and uridine rescued the cell proliferation of HT-29, HT-1080, M21 and MCF-7 cancer cell lines in the presence of SFOM-0046. Finally, molecular docking showed a binding pose of SFOM-0046 interacting with Met43 and Phe62 present in the brequinar-binding site. In conclusion, PUB-SOs and notably SFOM-0046 are new small molecules hDHODH inhibitors triggering replication stresses and S-phase arrest.
|
Cytotoxicity against human MDA-MB-231 cells assessed as reduction in cell viability incubated for 24 hrs by CellTiter-Glo luminescent assay
|
Homo sapiens
|
310.0
nM
|
|
|
Cytotoxicity against human MDA-MB-468 cells assessed as reduction in cell viability incubated for 24 hrs by CellTiter-Glo luminescent assay
|
Homo sapiens
|
82.0
nM
|
|
|
Inhibition of recombinant N-terminal His-tagged human DHODH (31 to 395 residues) expressed in Escherichia coli using DL-dihydroorotic acid as substrate and Q0 as coenzyme by DCIP based assay
|
Homo sapiens
|
5.0
nM
|
|
|
Inhibition of human recombinant full length C-terminal MYC/DDk-tagged DHODH using decylubiquinone as substrate at 30 uM measured for 1 hr by DCIP absorbance assay
|
Homo sapiens
|
68.0
%
|
|
|
Inhibition of human recombinant full length C-terminal MYC/DDk-tagged DHODH using decylubiquinone as substrate measured for 1 hr by DCIP absorbance assay
|
Homo sapiens
|
20.0
nM
|
|
|
Inhibition of human recombinant N-terminal GST-tagged DHODH expressed in Escherichia coli BL21(DE3) using dihydroorotate substrate preincubated for 5 mins followed by substrate addition by DCIP assay
|
Homo sapiens
|
1.8
nM
|
|
|
Induction of cell differentiation in human THP-1 cells assessed as CD14 expression after 3 days by flow cytometric analysis
|
Homo sapiens
|
248.6
nM
|
|
|
Induction of apoptosis in human THP-1 cells after 3 days by Annexin-V-FITC staining based flow cytometry
|
Homo sapiens
|
264.0
nM
|
|
|
Induction of cell differentiation in human U-937 cells assessed as CD11b expression after 3 days by flow cytometric analysis
|
Homo sapiens
|
188.6
nM
|
|
|
Induction of apoptosis in human U-937 cells after 3 days by Annexin-V-FITC staining based flow cytometry
|
Homo sapiens
|
322.2
nM
|
|
