| Description: |
CFI-402257 is a highly selective and orally bioavailable TTK and Mps1 inhibitor with Kis of 0.1 and 0.09 nM, respectively. |
| Target: |
Mps1:1.7 nM (IC50, TTK)
CYP2C9:13 μM (IC50)
CYP2C19:8 μM (IC50) |
| 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[2]. |
| 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 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[2]. |
| Cell Assay: |
Cells are treated with 20 pM to 10 μM CFI-402257 for 5 days. After 5 d, cell growth in each well is assessed by an SRB assay. SRB absorbance values are adjusted by subtracting the average of the baseline readings from untreated cells assessed 1 d after cell seeding. Relative cell growth is calculated by comparing vs. DMSO-treated cells. The concentrations at which cell growth is inhibited by 50% are calculated by using GraphPad Prism software[2]. |
| Animal Administration: |
Mice: CFI-402257 and the vehicle are administered by oral gavage, and carboplatin, anti–PD-1 antibody, and isotype control are administered by i.p. injection to mice as described earlier. Animal weights are monitored daily, and tumor volume is measured three times per week[2]. |
| 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. |
