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|Ref Type||Journal Article|
|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|
|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.|
|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|