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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 Vol Issue Date Pages Journal Short Title
Proceedings of the National Academy of Sciences of the United States of America 114 12 2017 Mar 21 3127-3132 Proc Natl Acad Sci U S A
URL
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
CFI-402257 CFI-402257 0 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
CFI-402257 MPS1 Inhibitor 27 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