| Description |
CFI-402257 hydrochloride is a highly selective and orally bioavailable TTK/Mps1 inhibitor with an IC50s of 1.7 nM for TTK in vitro. CFI-402257 hydrochloride has anti-cancer activity[1].
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| Related Catalog |
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| Target |
IC50: 1.7 nM (TTK in vitro)[1] EC50: 6.5 nM (Mps1)[2].
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| In Vitro |
CFI-402257 is highly selective to TTK. CFI-402257 is tested against a panel of human kinases at 1 μM and inhibits none of the 262 kinases tested. CFI-402257 is a potent inhibitor of cell growth[1]. CFI-402257 (200 nM, 6 h) causes a massive increase in chromosome missegregations[2]. CFI-402257 (0, 50 or 100 nM) induces a dose-dependent dysregulation of the cell cycle, resulting in an increase in the frequency of cells exhibiting an aneuploid DNA content[2]. CFI-402257 exhibits effects consistent with Mps1 kinase inhibition, specifically SAC inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death[2]. Cell Cycle Analysis[2] Cell Line: HCT116 cells. Concentration: 0 nM, 50 nM, 100 nM, 300 nM, 1000 nM, 3000 nM. Incubation Time: 48 hours Result: Resulted in an increase in the frequency of cells exhibiting an aneuploid DNA content. Western Blot Analysis[2] Cell Line: HCT116 cells. Concentration: 0 nM, 50 nM or 100 nM. Incubation Time: 8, 16, 24 and 48 hours. Result: CFI-402257-induced aneuploidy was accompanied by a progressive accumulation of apoptotic cells that were detectable as early as 16 h following treatment.
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| In Vivo |
CFI-402257 given orally QD shows dose-dependent activity in mice with established tumors from xenografted MDA-MB-231 human TNBC cells and MDA-MB-468 human TNBC cells in mice. CFI-402257 demonstrates antitumor activity in a platinum-resistant PDX model of high-grade serous ovarian cancer[2]. Animal Model: Xenografted MDA-MB-231 human TNBC cells and MDA-MB-468 human TNBC cells in mice[2]. Dosage: 5, 6 mg/kg. Administration: Oral gavage, daily. Result: Xenografted MDA-MB-231 human TNBC cells: 5 mg/kg, tumor growth inhibition (TGI) = 74%; 6 mg/kg, TGI = 89%. Xenografted MDA-MB-468 human TNBC cells: 5 mg/kg, tumor growth inhibition (TGI) = 75%; 6 mg/kg, TGI = 94%. Animal Model: PDX model of high-grade serous ovarian cancer[2]. Dosage: 6.5, 7.5 mg/kg. Administration: Oral gavage, daily. Result: 6.5 mg/kg, tumor growth inhibition (TGI) = 61%; 7.5 mg/kg, TGI = 97%.
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| References |
[1]. Liu Y, et al. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent. ACS Med Chem Lett. 2016 May 6;7(7):671-5. [2]. Mason JM, et al. Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132.
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