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Ref Type Journal Article
PMID (28270606)
Authors Mason JM, Wei X, Fletcher GC, Kiarash R, Brokx R, Hodgson R, Beletskaya I, Bray MR, Mak TW
Title Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.
Journal Proceedings of the National Academy of Sciences of the United States of America
Vol 114
Issue 12
Date 2017 Mar 21
Abstract Text Loss of cell-cycle control is a hallmark of human cancer. Cell-cycle checkpoints are essential for maintaining genome integrity and balanced growth and division. They are specifically deregulated in cancer cells and contain regulators that represent potential therapeutic targets. Monopolar spindle 1 (Mps1; also known as TTK protein kinase) is a core component of the spindle assembly checkpoint (SAC), a genome-surveillance mechanism that is important for cell survival, and has emerged as a candidate target for anticancer therapy. Here, we report the cellular and antitumor effects of CFI-402257, a potent (Mps1 Ki = 0.09 ± 0.02 nM; cellular Mps1 EC50 = 6.5 ± 0.5 nM), highly selective, and orally active small-molecule inhibitor of Mps1 that was identified through a drug-discovery program. Human cancer cells treated with CFI-402257 exhibit effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death. Oral administration of CFI-402257 in monotherapy or in combination with an anti-programmed cell death 1 (PD-1) antibody in mouse models of human cancer results in inhibition of tumor growth at doses that are well-tolerated. Our findings provide a rationale for the clinical evaluation of CFI-402257 in patients with solid tumors.


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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
CFI-402257 MPS1 Inhibitor 25 CFI-402257 selectively inhibits TTK (MPS1), resulting in chromosomal segregation errors, and potentially leading to decreased tumor cell growth (PMID: 28270606, PMID: 29378962).
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
Unknown unknown ovarian serous carcinoma not applicable CFI-402257 Preclinical - Pdx Actionable In a preclinical study, CFI-402257 growth in patient-derived xenograft (PDX) models of platinum-sensitive and platinum-resistant high-grade serous ovarian cancer (PMID: 28270606). 28270606
Unknown unknown colon carcinoma not applicable CFI-402257 + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, treatment with the combination of CFI-402257 and an anti-PD-1 antibody induced tumor regression in 2/8 tumors in syngeneic mouse models of colon carcinoma, and no regressions were demonstrated in mice treated with single agent CFI-402257 or anti-PD-1 antibody (PMID: 28270606). 28270606
Unknown unknown triple-receptor negative breast cancer not applicable CFI-402257 Preclinical - Cell line xenograft Actionable In a preclinical study, CFI-402257 inhibited growth of triple-negative breast cancer cell lines in culture, and inhibited tumor growth in xenograft models (PMID: 28270606). 28270606