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. 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.
|Cell lines||HCT116 cells|
|Preparation method||Cells were pretreated with 0.5 μM MG132 for 30 min before treatment with CFI-402257 or DMSO for 4 h. For cellular histone H3 (S10) EC50 determination, HCT116 cells were treated with 200 ng/mL nocodazole for 17 h before treatment with CFI-402257 or DMSO for 4 h.|
|Incubation time||17 h|
|Animal models||CD-1 nude mice|
|Formulation||10% (vol/vol) NMP/40% (vol/vol) PEG-300/50% (vol/vol) water|
|Dosages||10, 25, and 55 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||10 mM in DMSO|
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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