|
Inhibition of Farnesyltransferase
|
None
|
0.9
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and biological activity of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles as potent and selective farnesyltransferase inhibitors.
Year : 2004
Volume : 47
Issue : 3
First Page : 612
Last Page : 626
Authors : Wang L, Wang GT, Wang X, Tong Y, Sullivan G, Park D, Leonard NM, Li Q, Cohen J, Gu WZ, Zhang H, Bauch JL, Jakob CG, Hutchins CW, Stoll VS, Marsh K, Rosenberg SH, Sham HL, Lin NH.
Abstract : A novel series of 4-[(4-cyano-2-arylbenzyloxy)-(3-methyl-3H-imidazol-4-yl)methyl]benzonitriles have been synthesized as selective farnesyltransferase inhibitors using structure-based design. X-ray cocrystal structures of compound 20-FTase-HFP and A313326-FTase-HFP confirmed our initial design. The decreased interaction between the aryl groups and Ser 48 in GGTase-I binding site could be one possible reason to explain the improved selectivity for this new series of FTase inhibitors. Medicinal chemistry efforts led to the discovery of compound 64 with potent cellular activity (EC(50) = 3.5 nM) and outstanding pharmacokinetic profiles in dog (96% bioavailable, 18.4 h oral t(1/2), and 0.19 L/(h x kg) plasma clearance).
|
In vitro inhibitory activity against farnesyltransferase (FTase)
|
Bos taurus
|
0.57
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase.
Year : 2003
Volume : 13
Issue : 7
First Page : 1367
Last Page : 1371
Authors : Curtin ML, Florjancic AS, Cohen J, Gu WZ, Frost DJ, Muchmore SW, Sham HL.
Abstract : A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (<or=80nM). An X-ray crystal structure of inhibitor 21 bound to rat farnesyltransferase is also presented.
|
Inhibition of [3H]FPP incorporation into biotinylated lamin B peptide by farnesyl transferase
|
None
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA.
Year : 2003
Volume : 13
Issue : 24
First Page : 4361
Last Page : 4364
Authors : Angibaud P, Saha AK, Bourdrez X, End DW, Freyne E, Lezouret P, Mannens G, Mevellec L, Meyer C, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Venet M, Wouters W.
Abstract : Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
|
Inhibition of [3H]FPP incorporation into biotinylated laminB peptide by farnesyl transferase
|
None
|
0.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted azoloquinolines and -quinazolines as new potent farnesyl protein transferase inhibitors.
Year : 2003
Volume : 13
Issue : 24
First Page : 4365
Last Page : 4369
Authors : Angibaud P, Bourdrez X, End DW, Freyne E, Janicot M, Lezouret P, Ligny Y, Mannens G, Damsch S, Mevellec L, Meyer C, Muller P, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
|
Inhibition of [3H]FPP incorporation into biotinylated laminB peptide by farnesyl transferase
|
None
|
0.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors.
Year : 2003
Volume : 13
Issue : 9
First Page : 1543
Last Page : 1547
Authors : Angibaud P, Bourdrez X, Devine A, End DW, Freyne E, Ligny Y, Muller P, Mannens G, Pilatte I, Poncelet V, Skrzat S, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
|
Inhibitory concentration against farnesyltransferase was determined
|
Homo sapiens
|
0.86
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of farnesyltransferase: a rational approach to cancer chemotherapy?
Year : 2004
Volume : 47
Issue : 8
First Page : 1869
Last Page : 1878
Authors : Bell IM.
|
In vivo inhibition of T24ras-NIH3T3 tumor growth at 25 mg/kg in mice
|
Mus musculus
|
37.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors.
Year : 2003
Volume : 13
Issue : 9
First Page : 1543
Last Page : 1547
Authors : Angibaud P, Bourdrez X, Devine A, End DW, Freyne E, Ligny Y, Muller P, Mannens G, Pilatte I, Poncelet V, Skrzat S, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
|
T24H-ras-transformed NIH3T3 cell proliferation
|
Mus musculus
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted azoloquinolines and -quinazolines as new potent farnesyl protein transferase inhibitors.
Year : 2003
Volume : 13
Issue : 24
First Page : 4365
Last Page : 4369
Authors : Angibaud P, Bourdrez X, End DW, Freyne E, Janicot M, Lezouret P, Ligny Y, Mannens G, Damsch S, Mevellec L, Meyer C, Muller P, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
|
In vitro inhibition of NIH3T3 cell proliferation
|
Mus musculus
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA.
Year : 2003
Volume : 13
Issue : 24
First Page : 4361
Last Page : 4364
Authors : Angibaud P, Saha AK, Bourdrez X, End DW, Freyne E, Lezouret P, Mannens G, Mevellec L, Meyer C, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Venet M, Wouters W.
Abstract : Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
|
Inhibition of T24F1H-ras-transformation in NIH 3T3 cells
|
Mus musculus
|
1.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors.
Year : 2003
Volume : 13
Issue : 9
First Page : 1543
Last Page : 1547
Authors : Angibaud P, Bourdrez X, Devine A, End DW, Freyne E, Ligny Y, Muller P, Mannens G, Pilatte I, Poncelet V, Skrzat S, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.
|
In vivo inhibition of T24H-ras-NIH3T3 cell proliferation in mice
|
Mus musculus
|
37.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-methyl-1,2,4-triazol-3-yl heterocycle as an alternative to the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA.
Year : 2003
Volume : 13
Issue : 24
First Page : 4361
Last Page : 4364
Authors : Angibaud P, Saha AK, Bourdrez X, End DW, Freyne E, Lezouret P, Mannens G, Mevellec L, Meyer C, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Venet M, Wouters W.
Abstract : Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure-activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition.
|
Effective concentration against Ha-RAS processing in NIH3T3 ras-transformed cells
|
Mus musculus
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel and selective imidazole-containing biphenyl inhibitors of protein farnesyltransferase.
Year : 2003
Volume : 13
Issue : 7
First Page : 1367
Last Page : 1371
Authors : Curtin ML, Florjancic AS, Cohen J, Gu WZ, Frost DJ, Muchmore SW, Sham HL.
Abstract : A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (<or=80nM). An X-ray crystal structure of inhibitor 21 bound to rat farnesyltransferase is also presented.
|
In vivo inhibition of T24H-ras NIH3T3 tumor growth in mice
|
Mus musculus
|
37.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Substituted azoloquinolines and -quinazolines as new potent farnesyl protein transferase inhibitors.
Year : 2003
Volume : 13
Issue : 24
First Page : 4365
Last Page : 4369
Authors : Angibaud P, Bourdrez X, End DW, Freyne E, Janicot M, Lezouret P, Ligny Y, Mannens G, Damsch S, Mevellec L, Meyer C, Muller P, Pilatte I, Poncelet V, Roux B, Smets G, Van Dun J, Van Remoortere P, Venet M, Wouters W.
Abstract : A series of (4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)azoloquinolines and -quinazolines was prepared. These compounds displayed potent Farnesyl Protein Transferase inhibitory activity and tetrazolo[1,5-a]quinazolines are promising agents for oral in vivo inhibition.
|
Inhibition of Bovine farnesyltransferase (FTase)
|
Bos taurus
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5367
Last Page : 5370
Authors : Li Q, Claiborne A, Li T, Hasvold L, Stoll VS, Muchmore S, Jakob CG, Gu W, Cohen J, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described.
|
Inhibition of bovine farnesyltransferase
|
Bos taurus
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-aryl-1'-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5371
Last Page : 5376
Authors : Li Q, Wang GT, Li T, Gwaltney SL, Woods KW, Claiborne A, Wang X, Gu W, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.
|
Inhibition of bovine farnesyltransferase
|
Bos taurus
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.
Year : 2005
Volume : 15
Issue : 8
First Page : 2033
Last Page : 2039
Authors : Li Q, Woods KW, Wang W, Lin NH, Claiborne A, Gu WZ, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.
|
Inhibition of bovine farnesyl transferase in presence of Lonafarnib
|
Bos taurus
|
8.3
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.
Year : 2005
Volume : 15
Issue : 11
First Page : 2918
Last Page : 2922
Authors : Li Q, Li T, Woods KW, Gu WZ, Cohen J, Stoll VS, Galicia T, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.
|
Inhibition of bovine farnesyl transferase in presence of Tipifarnib
|
Bos taurus
|
0.65
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.
Year : 2005
Volume : 15
Issue : 11
First Page : 2918
Last Page : 2922
Authors : Li Q, Li T, Woods KW, Gu WZ, Cohen J, Stoll VS, Galicia T, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.
|
Inhibitory concentration against Protein farnesyltransferase of Trypanosoma cruzi
|
Trypanosoma cruzi
|
75.0
nM
|
|
Journal : J. Med. Chem.
Title : The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.
Year : 2005
Volume : 48
Issue : 17
First Page : 5415
Last Page : 5418
Authors : Hucke O, Gelb MH, Verlinde CL, Buckner FS.
Abstract : Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.
|
Inhibition of biotinylated lamin B peptide farnesylation by Plasmodium falciparum farnesyltransferase
|
Plasmodium falciparum
|
17.0
nM
|
|
Journal : J. Med. Chem.
Title : Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.
Year : 2005
Volume : 48
Issue : 11
First Page : 3704
Last Page : 3713
Authors : Nallan L, Bauer KD, Bendale P, Rivas K, Yokoyama K, Hornéy CP, Pendyala PR, Floyd D, Lombardo LJ, Williams DK, Hamilton A, Sebti S, Windsor WT, Weber PC, Buckner FS, Chakrabarti D, Gelb MH, Van Voorhis WC.
Abstract : New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THQ PFTIs with antimalaria activity.
|
Inhibition of Ras farnesylation in H-Ras transformed NIH3T3 cells
|
Mus musculus
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5367
Last Page : 5370
Authors : Li Q, Claiborne A, Li T, Hasvold L, Stoll VS, Muchmore S, Jakob CG, Gu W, Cohen J, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described.
|
Inhibition of H-Ras transformed NIH-3T3-cell proliferation
|
Mus musculus
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of 1-aryl-1'-imidazolyl methyl ethers as non-thiol farnesyltransferase inhibitors.
Year : 2004
Volume : 14
Issue : 21
First Page : 5371
Last Page : 5376
Authors : Li Q, Wang GT, Li T, Gwaltney SL, Woods KW, Claiborne A, Wang X, Gu W, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of imidazole-containing methyl ethers (4-5) have been designed and synthesized as potent and selective farnesyltransferase inhibitors (FTIs) by transposition of the D-ring to the methyl group on the imidazole of the previously reported FTIs 3. Several compounds such as 4h and 5b demonstrate superior enzymatic activity to the current benchmark compound tipifarnib (1) with IC(50) values in the lower subnanomolar range, while maintaining excellent cellular activity comparable to tipifarnib. The compounds are characterized as being simple, easier to make, and possess no chiral center involved.
|
Inhibition of Ras processing in H-ras transformed NIH3T3 cells in presence of Lonafarnib
|
Mus musculus
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.
Year : 2005
Volume : 15
Issue : 11
First Page : 2918
Last Page : 2922
Authors : Li Q, Li T, Woods KW, Gu WZ, Cohen J, Stoll VS, Galicia T, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.
|
Inhibition of Ras processing in H-ras transformed NIH3T3 cells in presence of Tipifarnib
|
Mus musculus
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity.
Year : 2005
Volume : 15
Issue : 11
First Page : 2918
Last Page : 2922
Authors : Li Q, Li T, Woods KW, Gu WZ, Cohen J, Stoll VS, Galicia T, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.
|
Percent inhibition of H-ras processing in transformed NIH3T3 cells at 100 nM
|
Mus musculus
|
1.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.
Year : 2005
Volume : 15
Issue : 8
First Page : 2033
Last Page : 2039
Authors : Li Q, Woods KW, Wang W, Lin NH, Claiborne A, Gu WZ, Cohen J, Stoll VS, Hutchins C, Frost D, Rosenberg SH, Sham HL.
Abstract : Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.
|
Inhibition of rat recombinant protein farnesyltransferase expressed in Sf9 cells by [3H]-scintillation proximity assay
|
Rattus norvegicus
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Rational modification of a candidate cancer drug for use against Chagas disease.
Year : 2009
Volume : 52
Issue : 6
First Page : 1639
Last Page : 1647
Authors : Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS.
Abstract : Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigotes expressing beta-galactosidase in mouse 3T3 fibroblast after 7 days by alamar blue assay
|
Trypanosoma cruzi
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Rational modification of a candidate cancer drug for use against Chagas disease.
Year : 2009
Volume : 52
Issue : 6
First Page : 1639
Last Page : 1647
Authors : Kraus JM, Verlinde CL, Karimi M, Lepesheva GI, Gelb MH, Buckner FS.
Abstract : Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14 alpha-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen infected in mouse 3T3 cells
|
Trypanosoma cruzi
|
4.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Isoquinoline-based analogs of the cancer drug clinical candidate tipifarnib as anti-Trypanosoma cruzi agents.
Year : 2009
Volume : 19
Issue : 23
First Page : 6582
Last Page : 6584
Authors : Chennamaneni NK, Arif J, Buckner FS, Gelb MH.
Abstract : We developed a synthetic route to prepare isoquinoline analogs of the cancer drug clinical candidate tipifarnib. We show that these compounds kill Trypanosoma cruzi amastigotes grown in mammalian host cells at concentrations in the low nanomolar range. These isoquinolines represent new leads for the development of drugs to treat Chagas disease.
|
Inhibition of rat recombinant PFT expressed in insect Sf9 cells by scintillation proximity assay
|
Rattus norvegicus
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
Year : 2010
Volume : 53
Issue : 10
First Page : 3887
Last Page : 3898
Authors : Kraus JM, Tatipaka HB, McGuffin SA, Chennamaneni NK, Karimi M, Arif J, Verlinde CL, Buckner FS, Gelb MH.
Abstract : We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
|
Antitrypanosomal activity against Trypanosoma cruzi Tulahuen amastigotes infected in rat 3T3 cells after 7 days by alamar blue assay
|
Trypanosoma cruzi
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
Year : 2010
Volume : 53
Issue : 10
First Page : 3887
Last Page : 3898
Authors : Kraus JM, Tatipaka HB, McGuffin SA, Chennamaneni NK, Karimi M, Arif J, Verlinde CL, Buckner FS, Gelb MH.
Abstract : We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14alpha-demethylase. Tipifarnib is an inhibitor of human protein farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14alpha-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability and acceptable pharmacokinetic properties, the newly discovered tipifarnib analogues are ideal leads for the development of drugs to treat Chagas disease.
|
Inhibition of FTase
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
SANGER: Inhibition of human NCI-H2009 cell growth in a cell viability assay.
|
Homo sapiens
|
363.36
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H2122 cell growth in a cell viability assay.
|
Homo sapiens
|
191.45
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H2342 cell growth in a cell viability assay.
|
Homo sapiens
|
379.83
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H650 cell growth in a cell viability assay.
|
Homo sapiens
|
773.09
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H727 cell growth in a cell viability assay.
|
Homo sapiens
|
874.26
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NKM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
774.18
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NMC-G1 cell growth in a cell viability assay.
|
Homo sapiens
|
425.05
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NTERA-S-cl-D1 cell growth in a cell viability assay.
|
Homo sapiens
|
237.44
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OAW-42 cell growth in a cell viability assay.
|
Homo sapiens
|
955.9
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OCUB-M cell growth in a cell viability assay.
|
Homo sapiens
|
471.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human P30-OHK cell growth in a cell viability assay.
|
Homo sapiens
|
263.88
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human QIMR-WIL cell growth in a cell viability assay.
|
Homo sapiens
|
16.31
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human REH cell growth in a cell viability assay.
|
Homo sapiens
|
59.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RPMI-6666 cell growth in a cell viability assay.
|
Homo sapiens
|
7.407
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RT-112 cell growth in a cell viability assay.
|
Homo sapiens
|
381.76
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SIG-M5 cell growth in a cell viability assay.
|
Homo sapiens
|
14.57
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-HEP-1 cell growth in a cell viability assay.
|
Homo sapiens
|
714.07
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-LMS-1 cell growth in a cell viability assay.
|
Homo sapiens
|
184.09
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-MEL-2 cell growth in a cell viability assay.
|
Homo sapiens
|
483.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SNG-M cell growth in a cell viability assay.
|
Homo sapiens
|
203.54
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SNU-423 cell growth in a cell viability assay.
|
Homo sapiens
|
704.66
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SNU-449 cell growth in a cell viability assay.
|
Homo sapiens
|
622.94
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SUP-T1 cell growth in a cell viability assay.
|
Homo sapiens
|
786.79
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW1710 cell growth in a cell viability assay.
|
Homo sapiens
|
725.5
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW620 cell growth in a cell viability assay.
|
Homo sapiens
|
482.24
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human T84 cell growth in a cell viability assay.
|
Homo sapiens
|
546.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human 786-0 cell growth in a cell viability assay.
|
Homo sapiens
|
341.56
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human 8305C cell growth in a cell viability assay.
|
Homo sapiens
|
976.31
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human 8505C cell growth in a cell viability assay.
|
Homo sapiens
|
431.09
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A3-KAW cell growth in a cell viability assay.
|
Homo sapiens
|
901.22
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A375 cell growth in a cell viability assay.
|
Homo sapiens
|
616.48
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A388 cell growth in a cell viability assay.
|
Homo sapiens
|
864.57
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A4-Fuk cell growth in a cell viability assay.
|
Homo sapiens
|
20.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A427 cell growth in a cell viability assay.
|
Homo sapiens
|
579.17
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A431 cell growth in a cell viability assay.
|
Homo sapiens
|
655.36
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ALL-PO cell growth in a cell viability assay.
|
Homo sapiens
|
554.56
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BB30-HNC cell growth in a cell viability assay.
|
Homo sapiens
|
585.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BC-1 cell growth in a cell viability assay.
|
Homo sapiens
|
129.96
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAL-12T cell growth in a cell viability assay.
|
Homo sapiens
|
760.04
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAL-148 cell growth in a cell viability assay.
|
Homo sapiens
|
884.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CAL-39 cell growth in a cell viability assay.
|
Homo sapiens
|
962.32
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TE-10 cell growth in a cell viability assay.
|
Homo sapiens
|
811.79
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TE-15 cell growth in a cell viability assay.
|
Homo sapiens
|
364.62
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TE-8 cell growth in a cell viability assay.
|
Homo sapiens
|
928.47
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TUR cell growth in a cell viability assay.
|
Homo sapiens
|
871.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human YKG-1 cell growth in a cell viability assay.
|
Homo sapiens
|
526.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CHL-1 cell growth in a cell viability assay.
|
Homo sapiens
|
805.46
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CMK cell growth in a cell viability assay.
|
Homo sapiens
|
151.45
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COLO-679 cell growth in a cell viability assay.
|
Homo sapiens
|
985.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human Calu-1 cell growth in a cell viability assay.
|
Homo sapiens
|
181.34
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DMS-273 cell growth in a cell viability assay.
|
Homo sapiens
|
719.89
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human Daoy cell growth in a cell viability assay.
|
Homo sapiens
|
57.53
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EFO-27 cell growth in a cell viability assay.
|
Homo sapiens
|
713.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ES6 cell growth in a cell viability assay.
|
Homo sapiens
|
539.35
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ETK-1 cell growth in a cell viability assay.
|
Homo sapiens
|
21.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-18 cell growth in a cell viability assay.
|
Homo sapiens
|
457.91
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human G-401 cell growth in a cell viability assay.
|
Homo sapiens
|
502.61
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human GDM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
352.39
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCC2157 cell growth in a cell viability assay.
|
Homo sapiens
|
323.16
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCC2998 cell growth in a cell viability assay.
|
Homo sapiens
|
384.36
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCT-15 cell growth in a cell viability assay.
|
Homo sapiens
|
327.05
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HEL cell growth in a cell viability assay.
|
Homo sapiens
|
394.49
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HH cell growth in a cell viability assay.
|
Homo sapiens
|
190.89
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HLE cell growth in a cell viability assay.
|
Homo sapiens
|
448.11
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HMV-II cell growth in a cell viability assay.
|
Homo sapiens
|
215.78
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HT-29 cell growth in a cell viability assay.
|
Homo sapiens
|
546.7
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HUTU-80 cell growth in a cell viability assay.
|
Homo sapiens
|
285.02
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human IA-LM cell growth in a cell viability assay.
|
Homo sapiens
|
47.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human IGROV-1 cell growth in a cell viability assay.
|
Homo sapiens
|
208.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KGN cell growth in a cell viability assay.
|
Homo sapiens
|
452.49
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KM12 cell growth in a cell viability assay.
|
Homo sapiens
|
116.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KS-1 cell growth in a cell viability assay.
|
Homo sapiens
|
770.35
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KU812 cell growth in a cell viability assay.
|
Homo sapiens
|
97.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KYSE-270 cell growth in a cell viability assay.
|
Homo sapiens
|
216.69
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KYSE-450 cell growth in a cell viability assay.
|
Homo sapiens
|
728.85
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KYSE-510 cell growth in a cell viability assay.
|
Homo sapiens
|
977.1
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LCLC-103H cell growth in a cell viability assay.
|
Homo sapiens
|
129.02
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LoVo cell growth in a cell viability assay.
|
Homo sapiens
|
240.91
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MCF7 cell growth in a cell viability assay.
|
Homo sapiens
|
166.3
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MEL-JUSO cell growth in a cell viability assay.
|
Homo sapiens
|
23.44
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MFH-ino cell growth in a cell viability assay.
|
Homo sapiens
|
814.5
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MIA-PaCa-2 cell growth in a cell viability assay.
|
Homo sapiens
|
320.4
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ML-2 cell growth in a cell viability assay.
|
Homo sapiens
|
13.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-16 cell growth in a cell viability assay.
|
Homo sapiens
|
258.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MV-4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
732.79
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MZ7-mel cell growth in a cell viability assay.
|
Homo sapiens
|
722.0
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NALM-6 cell growth in a cell viability assay.
|
Homo sapiens
|
36.21
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1299 cell growth in a cell viability assay.
|
Homo sapiens
|
693.08
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1355 cell growth in a cell viability assay.
|
Homo sapiens
|
973.77
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Inhibition of human FTase using farnesyl pyrophosphate as substrate by fluorescent assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : MedChemComm
Title : Discovery of novel inhibitors for human farnesyltransferase (hFTase) via structure-based virtual screening
Year : 2013
Volume : 4
Issue : 6
First Page : 962
Last Page : 971
Authors : Yu X, Zhao X, Zhu L, Zou C, Liu X, Zhao Z, Huang J, Li H
|
Inhibition of human recombinant FTase using [3H]farnesyldiphosphate
|
Homo sapiens
|
0.9
nM
|
|
Journal : MedChemComm
Title : Prenyltransferase Inhibitors: Treating Human Ailments from Cancer to Parasitic Infections.
Year : 2013
Volume : 4
Issue : 3
First Page : 476
Last Page : 492
Authors : Ochocki JD, Distefano MD.
Abstract : The posttranslational modification of protein prenylation is a covalent lipid modification on the C-terminus of substrate proteins that serves to enhance membrane affinity. Oncogenic proteins such as Ras have this modification and significant effort has been placed into developing inhibitors of the prenyltransferase enzymes for clinical therapy. In addition to cancer therapy, prenyltransferase inhibitors have begun to find important therapeutic uses in other diseases, including progeria, hepatitis C and D, parasitic infections, and other maladies. This review will trace the evolution of prenyltransferase inhibitors from their initial use as cancer therapeutics to their expanded applications for other diseases.
|
Inhibition of FTase isolated from Kirsten virus-transformed human osteosarcoma cells using K-rasB peptide as substrate in presence of [3H]farnesyl PPi by scintillation proximity assay
|
Homo sapiens
|
7.9
nM
|
|
Journal : J Med Chem
Title : Interrogating the Roles of Post-Translational Modifications of Non-Histone Proteins.
Year : 2018
Volume : 61
Issue : 8
First Page : 3239
Last Page : 3252
Authors : Buuh ZY, Lyu Z, Wang RE.
Abstract : Post-translational modifications (PTMs) allot versatility to the biological functions of highly conserved proteins. Recently, modifications to non-histone proteins such as methylation, acetylation, phosphorylation, glycosylation, ubiquitination, and many more have been linked to the regulation of pivotal pathways related to cellular response and stability. Due to the roles these dynamic modifications assume, their dysregulation has been associated with cancer and many other important diseases such as inflammatory disorders and neurodegenerative diseases. For this reason, we present a review and perspective on important post-translational modifications on non-histone proteins, with emphasis on their roles in diseases and small molecule inhibitors developed to target PTM writers. Certain PTMs' contribution to epigenetics has been extensively expounded; yet more efforts will be needed to systematically dissect their roles on non-histone proteins, especially for their relationships with nononcological diseases. Finally, current research approaches for PTM study will be discussed and compared, including limitations and possible improvements.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
20.28
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
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SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
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Severe acute respiratory syndrome coronavirus 2
|
18.57
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-3.427
%
|
|
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.
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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
|
2.29
%
|
|
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
|
0.57
%
|
|
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
|
0.57
%
|
|
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
|
2.29
%
|
|
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.
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Inhibition of C-terminal His6-tagged human recombinat FTase expressed in Escherichia coli BL21 RIL (DE3) cells using Dansyl-GCVLS peptide and farnesyl pyrophosphate as substrate measured for 15 mins by fluorimetric analysis
|
Homo sapiens
|
7.9
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Ultrasounds-mediated 10-seconds synthesis of chalcones as potential farnesyltransferase inhibitors.
Year : 2020
Volume : 30
Issue : 11
First Page : 127149
Last Page : 127149
Authors : Homerin G, Nica AS, Farce A, Dubois J, Ghinet A.
Abstract : A broad range of chalcones and derivatives were easily and rapidly synthesized, following Claisen-Schmidt condensation of (hetero)aryl ketones and (hetero)aryl aldehydes using a ultrasound probe. A comparison was made with classical magnetic stirring experiments, and an optimization study was realized, showing lithium hydroxide to be the best basic catalyst of the studied condensations. By-products of the reactions (β-hydroxy-ketone, diketones, and cyclohexanols) were also isolated. All compounds were evaluated in vitro for their ability to inhibit human farnesyltransferase, a protein implicated in cancer and rare diseases and on the NCI-60 cancer cell lines panel. Molecules showed inhibitory activity on the target protein and cytostatic effect on different cell lines with particular activity against MCF7, breast cancer cells.
