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ID: ALA5036336
Journal: J Med Chem
Title: Structure-Guided Optimization Provides a Series of TTK Protein Inhibitors with Potent Antitumor Activity.
Authors: Elsner J, Cashion D, Robinson D, Bahmanyar S, Tehrani L, Fultz KE, Narla RK, Peng X, Tran T, Apuy J, LeBrun L, Leftheris K, Boylan JF, Zhu D, Riggs JR.
Abstract: TTK is an essential spindle assembly checkpoint enzyme in many organisms. It plays a central role in tumor cell proliferation and is aberrantly overexpressed in a wide range of tumor types. We recently reported on a series of potent and selective TTK inhibitors with strong antiproliferative activity in triple negative breast cancer (TNBC) cell lines (8: TTK IC50 = 3.0 nM; CAL-51 IC50 = 84.0 nM). Inspired by previously described potent tricyclic TTK inhibitor 6 (TTK IC50 = 0.9 nM), we embarked on a structure-enabled design and optimization campaign to identify an improved series with excellent potency, TTK selectivity, solubility, CYP inhibition profile, and in vivo efficacy in a TNBC xenograft model. These efforts culminated in the discovery of 25 (TTK IC50 = 3.0 nM; CAL-51 IC50 = 16.0 nM), which showed significant single-agent efficacy when dosed iv in a TNBC xenograft model without body weight loss.
CiteXplore: 34459599