Reference Detail

Ref Type

Journal Article

PMID

(22929806)

Authors

Walton MI, Eve PD, Hayes A, Valenti MR, De Haven Brandon AK, Box G, Hallsworth A, Smith EL, Boxall KJ, Lainchbury M, Matthews TP, Jamin Y, Robinson SP, Aherne GW, Reader JC, Chesler L, Raynaud FI, Eccles SA, Collins I, Garrett MD

Title

CCT244747 is a novel potent and selective CHK1 inhibitor with oral efficacy alone and in combination with genotoxic anticancer drugs.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	18	20	2012 Oct 15	5650-61	Clin Cancer Res

URL

Abstract Text

Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity.Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay.CCT244747 inhibited cellular CHK1 activity (IC(50) 29-170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G(2) arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma.CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CCT244747	CCT244747	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CCT244747		SYN-1216	CHK1 Inhibitor 18	CCT244747 inhibits CHK1, potentially resulting in increased tumor cell death and increased sensitivity to other antitumor agents (PMID: 22929806, PMID: 27422809, PMID: 28131548).

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
CHEK1 positive	colon cancer	predicted - sensitive	CCT244747 + Gemcitabine	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of CCT244747 and Gemzar (gemcitabine) slowed tumor growth to a greater degree than treatment with either agent alone and decreased Chek1 phosphorylation in colon cancer cell line xenograft models (PMID: 22929806).	22929806