Reference Detail

Ref Type Journal Article
PMID (27167172)
Authors Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, Brown N, Walton MI, Eve PD, Boxall KJ, Hayes A, Henley AT, Valenti MR, De Haven Brandon AK, Box G, Jamin Y, Robinson SP, Westwood IM, van Montfort RL, Leonard PM, Lamers MB, Reader JC, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I
Title Multiparameter Lead Optimization to Give an Oral Checkpoint Kinase 1 (CHK1) Inhibitor Clinical Candidate: (R)-5-((4-((Morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyrazine-2-carbonitrile (CCT245737).
Journal Journal of medicinal chemistry
Vol 59
Issue 11
Date 2016 Jun 09
Abstract Text Multiparameter optimization of a series of 5-((4-aminopyridin-2-yl)amino)pyrazine-2-carbonitriles resulted in the identification of a potent and selective oral CHK1 preclinical development candidate with in vivo efficacy as a potentiator of deoxyribonucleic acid (DNA) damaging chemotherapy and as a single agent. Cellular mechanism of action assays were used to give an integrated assessment of compound selectivity during optimization resulting in a highly CHK1 selective adenosine triphosphate (ATP) competitive inhibitor. A single substituent vector directed away from the CHK1 kinase active site was unexpectedly found to drive the selective cellular efficacy of the compounds. Both CHK1 potency and off-target human ether-a-go-go-related gene (hERG) ion channel inhibition were dependent on lipophilicity and basicity in this series. Optimization of CHK1 cellular potency and in vivo pharmacokinetic-pharmacodynamic (PK-PD) properties gave a compound with low predicted doses and exposures in humans which mitigated the residual weak in vitro hERG inhibition.


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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
SRA737 SRA737 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
SRA737 CCT245737 CHK1 Inhibitor 14 SRA737 (CCT245737) is a selective oral inhibitor of CHK1, which may enhance sensitivity of tumor cells to chemotherapeutics, thereby resulting in increased antitumor activity (PMID: 27167172).
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
Unknown unknown lung non-small cell carcinoma not applicable Gemcitabine + SRA737 Preclinical - Cell line xenograft Actionable In a preclinical study, a non-small cell lung carcinoma cell line demonstrated sensitivity to the combination of SRA737 (CCT245737) and Gemzar (gemcitabine), resulting in antitumor efficacy in both culture and xenograft models (PMID: 27167172). 27167172
Unknown unknown colon cancer not applicable Gemcitabine + SRA737 Preclinical - Cell line xenograft Actionable In a preclinical study, Gemzar (gemcitabine) resulted in enhanced antitumor efficacy when combined with SRA737 (CCT245737) in a colon cancer cell line xenograft model (PMID: 27167172). 27167172