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Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)

[Image: see text] The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological...

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Autores principales: Reddy, M. V. Ramana, Akula, Balireddy, Cosenza, Stephen C., Athuluridivakar, Saikrishna, Mallireddigari, Muralidhar R., Pallela, Venkat R., Billa, Vinay K., Subbaiah, D. R. C. Venkata, Bharathi, E. Vijaya, Vasquez-Del Carpio, Rodrigo, Padgaonkar, Amol, Baker, Stacey J., Reddy, E. Premkumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983396/
https://www.ncbi.nlm.nih.gov/pubmed/24417566
http://dx.doi.org/10.1021/jm401073p
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author Reddy, M. V. Ramana
Akula, Balireddy
Cosenza, Stephen C.
Athuluridivakar, Saikrishna
Mallireddigari, Muralidhar R.
Pallela, Venkat R.
Billa, Vinay K.
Subbaiah, D. R. C. Venkata
Bharathi, E. Vijaya
Vasquez-Del Carpio, Rodrigo
Padgaonkar, Amol
Baker, Stacey J.
Reddy, E. Premkumar
author_facet Reddy, M. V. Ramana
Akula, Balireddy
Cosenza, Stephen C.
Athuluridivakar, Saikrishna
Mallireddigari, Muralidhar R.
Pallela, Venkat R.
Billa, Vinay K.
Subbaiah, D. R. C. Venkata
Bharathi, E. Vijaya
Vasquez-Del Carpio, Rodrigo
Padgaonkar, Amol
Baker, Stacey J.
Reddy, E. Premkumar
author_sort Reddy, M. V. Ramana
collection PubMed
description [Image: see text] The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure–activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30–100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure–activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound.
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spelling pubmed-39833962015-01-13 Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5) Reddy, M. V. Ramana Akula, Balireddy Cosenza, Stephen C. Athuluridivakar, Saikrishna Mallireddigari, Muralidhar R. Pallela, Venkat R. Billa, Vinay K. Subbaiah, D. R. C. Venkata Bharathi, E. Vijaya Vasquez-Del Carpio, Rodrigo Padgaonkar, Amol Baker, Stacey J. Reddy, E. Premkumar J Med Chem [Image: see text] The success of imatinib, a BCR-ABL inhibitor for the treatment of chronic myelogenous leukemia, has created a great impetus for the development of additional kinase inhibitors as therapeutic agents. However, the complexity of cancer has led to recent interest in polypharmacological approaches for developing multikinase inhibitors with low toxicity profiles. With this goal in mind, we analyzed more than 150 novel cyano pyridopyrimidine compounds and identified structure–activity relationship trends that can be exploited in the design of potent kinase inhibitors. One compound, 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x), was found to be the most active, inducing apoptosis of tumor cells at a concentration of approximately 30–100 nM. In vitro kinase profiling revealed that 7x is a multikinase inhibitor with potent inhibitory activity against the CDK4/CYCLIN D1 and ARK5 kinases. Here, we report the synthesis, structure–activity relationship, kinase inhibitory profile, in vitro cytotoxicity, and in vivo tumor regression studies by this lead compound. American Chemical Society 2014-01-13 2014-02-13 /pmc/articles/PMC3983396/ /pubmed/24417566 http://dx.doi.org/10.1021/jm401073p Text en Copyright © 2014 American Chemical Society
spellingShingle Reddy, M. V. Ramana
Akula, Balireddy
Cosenza, Stephen C.
Athuluridivakar, Saikrishna
Mallireddigari, Muralidhar R.
Pallela, Venkat R.
Billa, Vinay K.
Subbaiah, D. R. C. Venkata
Bharathi, E. Vijaya
Vasquez-Del Carpio, Rodrigo
Padgaonkar, Amol
Baker, Stacey J.
Reddy, E. Premkumar
Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title_full Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title_fullStr Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title_full_unstemmed Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title_short Discovery of 8-Cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a Potent Inhibitor of Cyclin-Dependent Kinase 4 (CDK4) and AMPK-Related Kinase 5 (ARK5)
title_sort discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (cdk4) and ampk-related kinase 5 (ark5)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983396/
https://www.ncbi.nlm.nih.gov/pubmed/24417566
http://dx.doi.org/10.1021/jm401073p
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