CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo.
OBJECTIVE
Chk1 kinase is a critical regulator of both S and G(2)-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124.


METHODS
CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models.


RESULTS
CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. It potently and selectively inhibits Chk1 in vitro (IC(50) = 0.0003 micromol/L). CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin or SN-38) in causing growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis. CHIR-124 abrogates the SN-38-induced S and G(2)-M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G(2)-M checkpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. We have also shown that CHIR-124 treatment can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating that Chk1 signaling is suppressed in the presence of CHIR-124. Finally, in an orthotopic breast cancer xenograft model, CHIR-124 potentiates the growth inhibitory effects of irinotecan by abrogating the G(2)-M checkpoint and increasing tumor apoptosis.


CONCLUSIONS
CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons.
Tse
Archie N
AN
Laboratory of New Drug Development, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Rendahl
Katherine G
KG
Sheikh
Tahir
T
Cheema
Haider
H
Aardalen
Kim
K
Embry
Millicent
M
Ma
Sylvia
S
Moler
Edward J
EJ
Ni
Zhi Jie
ZJ
Lopes de Menezes
Daniel E
DE
Hibner
Barbara
B
Gesner
Thomas G
TG
Schwartz
Gary K
GK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D011494:Protein Kinases / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage*; D011812:Quinuclidines / Q000008:administration & dosage*; D011897:Random Allocation; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; C518919:CHIR-124; D004791:Enzyme Inhibitors; D011804:Quinolines; D011812:Quinuclidines; D059004:Topoisomerase I Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse