Reference Detail

Ref Type Journal Article
PMID (17255282)
Authors Tse AN, Rendahl KG, Sheikh T, Cheema H, Aardalen K, Embry M, Ma S, Moler EJ, Ni ZJ, Lopes de Menezes DE, Hibner B, Gesner TG, Schwartz GK
Title CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 13
Issue 2 Pt 1
Date 2007 Jan 15
URL
Abstract Text 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.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.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.CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
CHIR-124 CHIR-124 is a selective inhibitor of CHK1, which may enhance sensitivity of tumor cells to chemotherapeutic agents (PMID: 17255282, PMID: 22244109).
Drug Name Trade Name Synonyms Drug Classes Drug Description
CHIR-124 CHK1 Inhibitor 14 CHIR-124 is a selective inhibitor of CHK1, which may enhance sensitivity of tumor cells to chemotherapeutic agents (PMID: 17255282, PMID: 22244109).
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 mutant breast carcinoma predicted - sensitive Camptothecin + CHIR-124 Preclinical - Cell culture Actionable In a preclinical study, the combination of Camptothecin and CHIR-124 demonstrated synergy in TP53-mutant breast carcinoma cell lines in culture, resulting in increased growth inhibition (PMID: 17255282). 17255282
TP53 loss colon cancer sensitive CHIR-124 + SN-38 Preclinical - Cell culture Actionable In a preclinical study, a colon cancer cell line deficient in TP53 demonstrated increased sensitivity to sequential treatment with SN-38 and CHIR-124 compared to cells with wild-type TP53, resulting in increased apoptosis and micronucleation in culture (PMID: 17255282). 17255282
TP53 inact mut breast carcinoma predicted - sensitive CHIR-124 + Irinotecan Preclinical - Cell line xenograft Actionable In a preclinical study, sequential treatment with Camptosaur (irinotecan) and CHIR-124 enhanced tumor growth inhibition compared to either agent alone in a breast carcinoma cell line xenograft model with defective TP53 (PMID: 17255282). 17255282
TP53 inact mut breast carcinoma predicted - sensitive CHIR-124 + SN-38 Preclinical - Cell culture Actionable In a preclinical study, SN-38 and CHIR-124 demonstrated synergy in a breast carcinoma cell line with defective TP53, resulting in increased cell cycle arrest and apoptosis in culture (PMID: 17255282). 17255282
TP53 mutant colon carcinoma predicted - sensitive Camptothecin + CHIR-124 Preclinical - Cell culture Actionable In a preclinical study, the combination of Camptothecin and CHIR-124 demonstrated synergy in TP53-mutant colon carcinoma cell lines in culture, resulting in increased growth inhibition (PMID: 17255282). 17255282