title: Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1.
abstract: Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G(1) checkpoint. In these tumors, however, the S-G(2) checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a "synthetic lethal" response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K(i) of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents.
authors: Department of Cancer Biology, Pfizer Global Research & Development, 10724 Science Center Drive, San Diego, CA 92121, USA. alessandra.blasina@pfizer.com
authors: Alessandra
authors: A
authors: Blasina
authors: Jill
authors: J
authors: Hallin
authors: Enhong
authors: E
authors: Chen
authors: Maria Elena
authors: ME
authors: Arango
authors: Eugenia
authors: E
authors: Kraynov
authors: James
authors: J
authors: Register
authors: Stephan
authors: S
authors: Grant
authors: Sacha
authors: S
authors: Ninkovic
authors: Ping
authors: P
authors: Chen
authors: Tim
authors: T
authors: Nichols
authors: Patrick
authors: P
authors: O'Connor
authors: Kenna
authors: K
authors: Anderes
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001570:Benzodiazepinones / Q000494:pharmacology*; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D002853:Chromatography, Liquid; D004249:DNA Damage; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D000093542:Gemcitabine
chemical_list: D001570:Benzodiazepinones; D006657:Histones; C532366:PF 00477736; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D000093542:Gemcitabine