CFI-402257 is an orally bioavailable inhibitor of monopolar spindle 1 (MPS1/TTK) kinase (IC50 = 1.7 nM). CFI-402257 is selective for MPS1/TTK over a panel of 262 kinases at a concentration of 1 μM. CFI-402257 increases aneuploidy in HCT116 cells when used at concentrations greater than 100 nM. It inhibits cell growth in a panel of breast, ovarian, prostate, pancreatic, lung, and colon cancer cell lines (GI50s = 0.001-1.3 μM). CFI-402257 (6.5 mg/kg) reduces tumor growth in HCT116 and HT29 mouse xenograft models as well as platinum-resistant and -sensitive high-grade serous ovarian cancer patient-derived xenograft (PDX) mouse models. It also inhibits the cytochrome P450 (CYP) isoforms CYP2C9 and CYP2C19 (IC50s = 13 and 8 μM, respectively) as well as CYP3A4 metabolism of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) and dibenzylfluorescein (DBF; IC50s = 0.51 and 14 μM, respectively).
CAS Number: 1610759-22-2
Molecular Weight: 498.58
Related CAS Number:
Chemical Name: Benzamide, N-cyclopropyl-4-[7-[[(cis-3-hydroxy-3-methylcyclobutyl)methyl]amino]-5-(3-pyridinyloxy)pyrazolo[1, 5-a]pyrimidin-3-yl]-2-methyl-
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
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. CFI-402257 shows strong antineoplastic activity on a broad panel of human cancer-derived cell lines, and causes effects consistent with depletion or inhibition of Mps1. CFI-402257 inhibits Mps1 with an IC50 value of 1.2 nM, and is ATP competitive with a Ki value of 0.09 nM. CFI-402257 inhibits autophosphorylation of Mps1 at threonine 12/serine 15 with an EC50 value of 6.5 nM in cells exogenously expressing human Mps1. CFI-402257 exerts potent growth inhibitory activity across the vast majority of cell lines with a median IC50 value of 15 nM. In vivo: The upper dose level for once-daily administration of CFI-402257 is between 6 and 6.5 mg/kg. CFI-402257 given orally QD shows dose-dependent activity in mice with established tumors from xenografted MDA-MB-231 human TNBC cells [5 mg/kg CFI-402257, tumor growth inhibition (TGI)=74%; 6 mg/kg, TGI=89%], from xenografted MDA-MB-468 human TNBC cells in mice (5 mg/kg, TGI=75%; 6 mg/kg, TGI=94%). CFI-402257 also demonstrates antitumor activity in a platinum-resistant PDX model of high-grade serous ovarian cancer (6.5 mg/kg, TGI=61%). CFI-402257 is found to be similarly efficacious in a platinum-sensitive PDX model of high-grade serous ovarian cancer.
- Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer. Mason JM, et al. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):3127-3132. PMID: 28270606.
- Discovery of Pyrazolo[1, 5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent. Liu Y, et al. ACS Med Chem Lett. 2016 May 6;7(7):671-5. PMID: 27437075.
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