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|Ref Type||Journal Article|
|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|
|Issue||2 Pt 1|
|Date||2007 Jan 15|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CHIR-124||CHIR124||CHK1 Inhibitor 15||CHIR-124 is a selective inhibitor of CHK1, which may enhance sensitivity of tumor cells to chemotherapeutic agents (PMID: 17255282, PMID: 22244109).|
|Gene||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 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 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|
|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 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|