|
Inhibition of GST-tagged EGFR expressed in sf9 cells by ELISA
|
None
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Irreversible protein kinase inhibitors: balancing the benefits and risks.
Year : 2012
Volume : 55
Issue : 14
First Page : 6243
Last Page : 6262
Authors : Barf T, Kaptein A.
|
Inhibition of GST-tagged ErbB2 expressed in sf9 cells by ELISA
|
None
|
46.0
nM
|
|
Journal : J. Med. Chem.
Title : Irreversible protein kinase inhibitors: balancing the benefits and risks.
Year : 2012
Volume : 55
Issue : 14
First Page : 6243
Last Page : 6262
Authors : Barf T, Kaptein A.
|
Inhibition of GST-tagged ErbB4 expressed in sf9 cells by ELISA
|
None
|
74.0
nM
|
|
Journal : J. Med. Chem.
Title : Irreversible protein kinase inhibitors: balancing the benefits and risks.
Year : 2012
Volume : 55
Issue : 14
First Page : 6243
Last Page : 6262
Authors : Barf T, Kaptein A.
|
Inhibition of wild type EGFR phosphorylation in human LoVo cells after 2 hrs by fluorescence assay
|
Homo sapiens
|
11.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).
Year : 2013
Volume : 56
Issue : 17
First Page : 7025
Last Page : 7048
Authors : Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross DA, Dakin LA, Debreczeni JÉ, Eberlein C, Finlay MR, Hill GB, Grist M, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ.
Abstract : A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
|
Inhibition of EGFR exon 19 deletion activating mutant phosphorylation in human PC9 cells after 2 hrs by fluorescence assay
|
Homo sapiens
|
0.63
nM
|
|
Journal : J. Med. Chem.
Title : Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).
Year : 2013
Volume : 56
Issue : 17
First Page : 7025
Last Page : 7048
Authors : Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross DA, Dakin LA, Debreczeni JÉ, Eberlein C, Finlay MR, Hill GB, Grist M, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ.
Abstract : A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
|
Inhibition of EGFR L858R/T970M double mutant phosphorylation in human NCI-H1975 cells after 2 hrs by fluorescence assay
|
Homo sapiens
|
42.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure- and reactivity-based development of covalent inhibitors of the activating and gatekeeper mutant forms of the epidermal growth factor receptor (EGFR).
Year : 2013
Volume : 56
Issue : 17
First Page : 7025
Last Page : 7048
Authors : Ward RA, Anderton MJ, Ashton S, Bethel PA, Box M, Butterworth S, Colclough N, Chorley CG, Chuaqui C, Cross DA, Dakin LA, Debreczeni JÉ, Eberlein C, Finlay MR, Hill GB, Grist M, Klinowska TC, Lane C, Martin S, Orme JP, Smith P, Wang F, Waring MJ.
Abstract : A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.
|
Inhibition of EGFR (unknown origin) by ELISA method
|
Homo sapiens
|
1.8
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Structure-activity study of quinazoline derivatives leading to the discovery of potent EGFR-T790M inhibitors.
Year : 2015
Volume : 102
First Page : 445
Last Page : 463
Authors : Zhang L, Yang Y, Zhou H, Zheng Q, Li Y, Zheng S, Zhao S, Chen D, Fan C.
Abstract : We have developed a series of 6, 7-disubstituted-4-(arylamino) quinazoline derivatives that functioned as irreversible EGFR inhibitors, and these compounds exhibited excellent enzyme inhibition potency. As compared with afatinib, some of them showed significantly enhanced activities towards H1975 cells (EGFR-T790M). Furthermore, the optimized compounds 7q and 8f also demonstrated good pharmacokinetic profiles, oral bioavailability as well as excellent in vivo efficacy in H1975 and HCC827 xenografts at a non-toxic dose. Based on the improved safety and efficacy against EGFR-T790M resistance, 7q and 8f are promising candidates for further studies.
|
ELISA-Based Kinase Assay: Inhibition of erbB tyrosine kinase activity was assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 uM ATP, test compound or vehicle control and 1-5 nM GST-erbB per 50 uL reaction) were run in 96-well plates coated with 0.25 mg/ml poly-Glu-Tyr (Sigma). The reactions were incubated for 6 minutes at room temperature while shaking. Kinase reactions were stopped by removal of reaction mixture, then wells were washed with wash buffer comprising 3% Bovine Serum Albumin and 0.1% Tween 20 in Phosphate Buffered Saline (PBS). Phosphorylated tyrosine residues were detected by adding 0.2 μg/ml anti-phosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to Horse Radish Peroxidase (HRP) for 25 minutes while shaking at room temperature.
|
Homo sapiens
|
6.9
nM
|
|
Title : 4-phenylamino-quinazolin-6-yl-amides
Year : 2014
|
ELISA-Based Kinase Assay: Inhibition of erbB tyrosine kinase activity was assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 uM ATP, test compound or vehicle control and 1-5 nM GST-erbB per 50 uL reaction) were run in 96-well plates coated with 0.25 mg/ml poly-Glu-Tyr (Sigma). The reactions were incubated for 6 minutes at room temperature while shaking. Kinase reactions were stopped by removal of reaction mixture, then wells were washed with wash buffer comprising 3% Bovine Serum Albumin and 0.1% Tween 20 in Phosphate Buffered Saline (PBS). Phosphorylated tyrosine residues were detected by adding 0.2 μg/ml anti-phosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to Horse Radish Peroxidase (HRP) for 25 minutes while shaking at room temperature.
|
Homo sapiens
|
83.67
nM
|
|
Title : 4-phenylamino-quinazolin-6-yl-amides
Year : 2014
|
Irreversible inhibition of GST-tagged ERBB1 (unknown origin) (Met-668 to Ala-1211 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Irreversible inhibition of GST-tagged ERBB2 (unknown origin) (Ile-675 to Val-1256 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA
|
Homo sapiens
|
46.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Irreversible inhibition of GST-tagged ERBB4 (unknown origin) (Gly-259 to Gly-690 residues) expressed in baculovirus infected Sf9 insect cells assessed as reduction in Glu/Tyr copolymer phosphorylation after 6 mins by ELISA
|
Homo sapiens
|
74.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Irreversible inhibition of full length human ERBB1 autophosphorylation transfected in EGF-stimulated mouse NIH/3T3 cells incubated for 2 hrs followed by stimulation with EGF for 10 mins
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Inhibition of LCK (unknown origin)
|
Homo sapiens
|
94.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Inhibition of Src (unknown origin)
|
Homo sapiens
|
110.0
nM
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
Inhibition of erbB1 phosphorylation in orally dosed severe combined immunodeficiency mouse xenografted with human SKOV3 cells administered daily for 14 days
|
Mus musculus
|
99.0
%
|
|
Journal : J Med Chem
Title : Tyrosine Kinase Inhibitors. 20. Optimization of Substituted Quinazoline and Pyrido[3,4-d]pyrimidine Derivatives as Orally Active, Irreversible Inhibitors of the Epidermal Growth Factor Receptor Family.
Year : 2016
Volume : 59
Issue : 17
First Page : 8103
Last Page : 8124
Authors : Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL, Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FO, Palmer BD, Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A.
Abstract : Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
|
ELISA-Based Kinase Assay: Inhibition of erbB tyrosine kinase activity was assessed using an ELISA-based receptor tyrosine kinase assay. Kinase reactions (50 mM HEPES, pH 7.4, 125 mM NaCl, 10 mM MgCl2, 100 μM sodium orthovanadate, 2 mM dithiothreitol, 20 uM ATP, test compound or vehicle control and 1-5 nM GST-erbB per 50 uL reaction) were run in 96-well plates coated with 0.25 mg/ml poly-Glu-Tyr (Sigma). The reactions were incubated for 6 minutes at room temperature while shaking. Kinase reactions were stopped by removal of reaction mixture, then wells were washed with wash buffer comprising 3% Bovine Serum Albumin and 0.1% Tween 20 in Phosphate Buffered Saline (PBS). Phosphorylated tyrosine residues were detected by adding 0.2 μg/ml anti-phosphotyrosine antibody (Oncogene Ab-4; 50 μL/well) coupled to Horse Radish Peroxidase (HRP) for 25 minutes while shaking at room temperature.
|
None
|
16.7
nM
|
|
Title : 4-phenylamino-quinazolin-6-yl-amides
Year : 2014
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
5.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
168.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.
|
Homo sapiens
|
988.0
nM
|
|
Journal : Science
Title : The target landscape of clinical kinase drugs.
Year : 2017
Volume : 358
Issue : 6367
Authors : Klaeger S, Heinzlmeir S and Wilhelm M et al
Abstract : Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.
|
Antiproliferative activity against human NCI-H1975 cells expressing EGFR T790M/L858R mutant incubated for 72 hrs by MTS assay
|
Homo sapiens
|
440.0
nM
|
|
Journal : Eur J Med Chem
Title : How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors.
Year : 2017
Volume : 142
First Page : 131
Last Page : 151
Authors : Milik SN, Lasheen DS, Serya RAT, Abouzid KAM.
Abstract : Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.
|
Inhibition of GST-tagged human EGFR catalytic domain expressed in insect cells
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors.
Year : 2017
Volume : 142
First Page : 131
Last Page : 151
Authors : Milik SN, Lasheen DS, Serya RAT, Abouzid KAM.
Abstract : Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.
|
Inhibition of GST-tagged human HER2 catalytic domain expressed in insect cells
|
Homo sapiens
|
45.7
nM
|
|
Journal : Eur J Med Chem
Title : How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors.
Year : 2017
Volume : 142
First Page : 131
Last Page : 151
Authors : Milik SN, Lasheen DS, Serya RAT, Abouzid KAM.
Abstract : Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.
|
Antiproliferative activity against human NCI-H1819 cells expressing wild type HER2 incubated for 72 hrs by MTS assay
|
Homo sapiens
|
29.0
nM
|
|
Journal : Eur J Med Chem
Title : How to train your inhibitor: Design strategies to overcome resistance to Epidermal Growth Factor Receptor inhibitors.
Year : 2017
Volume : 142
First Page : 131
Last Page : 151
Authors : Milik SN, Lasheen DS, Serya RAT, Abouzid KAM.
Abstract : Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.
|
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
|
85.54
%
|
|
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.
|
Inhibition of human GST-fused EGFR kinase domain expressed in baculovirus expression system measured after 30 mins by ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg Med Chem
Title : The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton.
Year : 2019
Volume : 27
Issue : 3
First Page : 568
Last Page : 577
Authors : Li Y, Xiao J, Zhang Q, Yu W, Liu M, Guo Y, He J, Liu Y.
Abstract : Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives. Thus, several studies have been approved for the use of quinazoline derivatives as inhibitors of other kinases, including Src and histone deacetylase. The aim of the present review was to summarize the mechanism of quinazoline compounds as PK inhibitors, their biological structure-activity relationship such as the substituted quinazoline compounds with different functional groups in the apoptotic process, and their effect on the proliferation of tumor cells. The development of novel agents based on the antitumor functions of quinazoline molecular compounds may improve the clinical outcomes of the affected population, particularly in patients with cancer.
|
Inhibition of human GST-fused HER2 kinase domain expressed in baculovirus expression system measured after 30 mins by ELISA
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg Med Chem
Title : The association between anti-tumor potency and structure-activity of protein-kinases inhibitors based on quinazoline molecular skeleton.
Year : 2019
Volume : 27
Issue : 3
First Page : 568
Last Page : 577
Authors : Li Y, Xiao J, Zhang Q, Yu W, Liu M, Guo Y, He J, Liu Y.
Abstract : Quinazoline was originally utilized as an anti-tumor treatment, and its various derivatives can be directly extracted from plants. In recent years, protein kinases (PK) have been well recognized in the development of tumor drugs. Functionally, PK serves a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of tumor cells. Due to its good physicochemical properties, quinazoline skeleton, a superior type of PK inhibitor, has been extensively used in anti-tumor drug design. An increasing number of studies on quinazoline synthesis have been reported and used by different groups to effectively develop novel derivatives. Thus, several studies have been approved for the use of quinazoline derivatives as inhibitors of other kinases, including Src and histone deacetylase. The aim of the present review was to summarize the mechanism of quinazoline compounds as PK inhibitors, their biological structure-activity relationship such as the substituted quinazoline compounds with different functional groups in the apoptotic process, and their effect on the proliferation of tumor cells. The development of novel agents based on the antitumor functions of quinazoline molecular compounds may improve the clinical outcomes of the affected population, particularly in patients with cancer.
|
Inhibition of EGFR (unknown origin) expressed in insect cells by ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advancements of 4-aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry.
Year : 2019
Volume : 170
First Page : 55
Last Page : 72
Authors : Das D, Hong J.
Abstract : The 4-aminoquinazoline core is an interesting pharmacophore and its applications in medicinal chemistry are wide spread. The core has been used for making many kinase inhibitors in past few years. Many researcher demonstrated 4-aminoquinazoline derivatives as specific kinase inhibitors, including tyrosine kinase and serine/theronine kinases. A number of anticancer drugs with 4-aminoquinazoline core are in the market, e.g. gefitinib, erlotinib, afatinib, lapatinib, decomitinib etc. 4-aminoquinazoline derivatives are applied for target specific treatment of lung, breast, colon, prostate cancers. In this review, we discussed the current development of 4-aminoquinazoline derivatives as kinase inhibitors and their uses as anticancer agents in recent years.
|
Inhibition of HER2 (unknown origin) expressed in insect cells by ELISA
|
Homo sapiens
|
45.7
nM
|
|
Journal : Eur J Med Chem
Title : Recent advancements of 4-aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry.
Year : 2019
Volume : 170
First Page : 55
Last Page : 72
Authors : Das D, Hong J.
Abstract : The 4-aminoquinazoline core is an interesting pharmacophore and its applications in medicinal chemistry are wide spread. The core has been used for making many kinase inhibitors in past few years. Many researcher demonstrated 4-aminoquinazoline derivatives as specific kinase inhibitors, including tyrosine kinase and serine/theronine kinases. A number of anticancer drugs with 4-aminoquinazoline core are in the market, e.g. gefitinib, erlotinib, afatinib, lapatinib, decomitinib etc. 4-aminoquinazoline derivatives are applied for target specific treatment of lung, breast, colon, prostate cancers. In this review, we discussed the current development of 4-aminoquinazoline derivatives as kinase inhibitors and their uses as anticancer agents in recent years.
|
Antiproliferative activity against human UCH1 cells measured after 72 hrs by alamar blue assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : J Med Chem
Title : Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma.
Year : 2019
Volume : 62
Issue : 9
First Page : 4772
Last Page : 4778
Authors : Asquith CRM, Naegeli KM, East MP, Laitinen T, Havener TM, Wells CI, Johnson GL, Drewry DH, Zuercher WJ, Morris DC.
Abstract : We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.
|
Inhibition of EGFR in human A431 cells assessed as reduction in EGF-stimulated EGFR autophosphorylation preincuabted for 90 mins followed by EGF-stimulation by sandwich-ELISA
|
Homo sapiens
|
6.0
nM
|
|
Journal : J Med Chem
Title : Design of a Cyclin G Associated Kinase (GAK)/Epidermal Growth Factor Receptor (EGFR) Inhibitor Set to Interrogate the Relationship of EGFR and GAK in Chordoma.
Year : 2019
Volume : 62
Issue : 9
First Page : 4772
Last Page : 4778
Authors : Asquith CRM, Naegeli KM, East MP, Laitinen T, Havener TM, Wells CI, Johnson GL, Drewry DH, Zuercher WJ, Morris DC.
Abstract : We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.17
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-5.829
%
|
|
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
|
-0.34
%
|
|
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
|
-0.43
%
|
|
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
|
-0.43
%
|
|
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
|
-0.34
%
|
|
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 BT-474 cells
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Antiproliferative activity against human SK-BR-3 cells
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2,4-diaryl pyrimidine derivatives as selective EGFR inhibitors.
Year : 2021
Volume : 212
First Page : 113019
Last Page : 113019
Authors : Li J,An B,Song X,Zhang Q,Chen C,Wei S,Fan R,Li X,Zou Y
Abstract : Lung cancer is the leading cause of cancer deaths. It has been demonstrated that epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are efficacious in patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this work, a new series of 2,4-diaryl pyrimidine derivatives containing cyclopropyl moiety were designed, synthesized and evaluated as novel selective EGFR inhibitors. The most promising compound, 8l demonstrated excellent kinase inhibitory activity against EGFR double mutation with IC value of 0.26 nM. Moreover, 8l provided strong activity against H1975 cells with IC value of 0.008 μM and exhibited little toxicity toward four non-tumorigenic cell lines. Furthermore, 8l showed potent anti-tumor efficacy in a murine EGFR-driven H1975 xenograft model. These results indicated that 8l may be a promising drug candidate for further study.
|
Inhibition of EGFR (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors.
Year : 2020
Volume : 28
Issue : 18
First Page : 115657
Last Page : 115657
Authors : Srour AM,Ahmed NS,Abd El-Karim SS,Anwar MM,El-Hallouty SM
Abstract : Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.
|
Inhibition of EGFR (unknown origin)
|
Homo sapiens
|
6.0
nM
|
|
