title: Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer.
abstract: 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 (Mps1Ki= 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.
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Mason
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Graham C
authors.initials: GC
authors.lastname: Fletcher
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Reza
authors.initials: R
authors.lastname: Kiarash
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Richard
authors.initials: R
authors.lastname: Brokx
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Richard
authors.initials: R
authors.lastname: Hodgson
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Irina
authors.initials: I
authors.lastname: Beletskaya
authors.affiliation: The Campbell Family Institute Therapeutics Group at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 1L7.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Bray
authors.affiliation: The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada M5G 2M9 tmak@uhnres.utoronto.ca.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C000625147:CFI-402257; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C075840:TTK protein, human
keywords: CFI-402257; Mps1/TTK; cancer; inhibitor