title: Pyrazolobenzodiazepines: part I. Synthesis and SAR of a potent class of kinase inhibitors.
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.
authors.affiliation: Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. jin-jun.liu@roche.com
authors.forename: Jin-Jun
authors.initials: JJ
authors.lastname: Liu
authors.forename: Irena
authors.initials: I
authors.lastname: Daniewski
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Ding
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.forename: Grace
authors.initials: G
authors.lastname: Ju
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Fred
authors.initials: F
authors.lastname: Konzelmann
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.forename: Giacomo
authors.initials: G
authors.lastname: Pizzolato
authors.forename: Pamela
authors.initials: P
authors.lastname: Rossman
authors.forename: Amy
authors.initials: A
authors.lastname: Swain
authors.forename: Kshitij
authors.initials: K
authors.lastname: Thakkar
authors.forename: Chung-Chen
authors.initials: CC
authors.lastname: Wei
authors.forename: Dorota
authors.initials: D
authors.lastname: Miklowski
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yin
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wovkulich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D001569:Benzodiazepines; D051357:Cyclin-Dependent Kinase 2