Pyrazolobenzodiazepines: Part I. Synthesis and SAR of a potent class of kinase inhibitors |
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| Authors: | Jin-Jun Liu Irena Daniewski Qingjie Ding Brian Higgins Grace Ju Kenneth Kolinsky Fred Konzelmann Christine Lukacs Giacomo Pizzolato Pamela Rossman Amy Swain Kshitij Thakkar Chung-Chen Wei Dorota Miklowski Hong Yang Xuefeng Yin Peter M Wovkulich |
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| Institution: | 1. Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland St. Nutley, NJ 07110, USA;2. Discovery Oncology, Hoffmann-La Roche Inc., 340 Kingsland St. Nutley, NJ 07110, USA |
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| Abstract: | A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure–activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents. |
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