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Article: Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

TitleFunctional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer
Authors
KeywordsMps1/TTK
Inhibitor
CFI-402257
Cancer
Issue Date2017
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2017, v. 114, n. 12, p. 3127-3132 How to Cite?
AbstractLoss 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 withMps1 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.
Persistent Identifierhttp://hdl.handle.net/10722/293009
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMason, Jacqueline M.-
dc.contributor.authorWei, Xin-
dc.contributor.authorFletcher, Graham C.-
dc.contributor.authorKiarash, Reza-
dc.contributor.authorBrokx, Richard-
dc.contributor.authorHodgson, Richard-
dc.contributor.authorBeletskaya, Irina-
dc.contributor.authorBray, Mark R.-
dc.contributor.authorMak, Tak W.-
dc.date.accessioned2020-11-17T14:57:41Z-
dc.date.available2020-11-17T14:57:41Z-
dc.date.issued2017-
dc.identifier.citationProceedings of the National Academy of Sciences of the United States of America, 2017, v. 114, n. 12, p. 3127-3132-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/293009-
dc.description.abstractLoss 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 withMps1 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.-
dc.languageeng-
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America-
dc.subjectMps1/TTK-
dc.subjectInhibitor-
dc.subjectCFI-402257-
dc.subjectCancer-
dc.titleFunctional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer-
dc.typeArticle-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1700234114-
dc.identifier.pmid28270606-
dc.identifier.pmcidPMC5373378-
dc.identifier.scopuseid_2-s2.0-85016110814-
dc.identifier.volume114-
dc.identifier.issue12-
dc.identifier.spage3127-
dc.identifier.epage3132-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000396893600061-
dc.identifier.issnl0027-8424-

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