title: Discovery of 1,4-dihydroindeno[1,2-c]pyrazoles as a novel class of potent and selective checkpoint kinase 1 inhibitors.
abstract: A new class of checkpoint kinase 1 (CHK-1) inhibitors bearing a 1,4-dihydroindeno[1,2-c]pyrazole core was developed after initial hits from high throughput screening. The efficient hit-to-lead process was facilitated by X-ray crystallography and led to potent inhibitors (<10nM) against CHK-1. X-ray co-crystal structures of bound inhibitors demonstrated that two sub-series of this class of compounds, exemplified by 21 and 41, exhibit distinctive hydrogen bonding patterns in the specificity pocket of the active site. Two compounds, 41 and 43, were capable of potentiating doxorubicin and camptothecin, both DNA-damaging agents, in cell proliferation assays (MTS and soft agar assays) and abrogating G2/M checkpoint in a mechanism-based FACS assay.
authors.affiliation: Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, IL 60064, USA. yunsong.tong@abbott.com
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Zehan
authors.initials: Z
authors.lastname: Chen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Credo
authors.forename: Wen-Zhen
authors.initials: WZ
authors.lastname: Gu
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gwaltney
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sowin
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002166:Camptothecin