Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.
Basic Information
ID: ALA4346709
Journal: J Med Chem
Title: Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.
Authors: Riggs JR, Elsner J, Cashion D, Robinson D, Tehrani L, Nagy M, Fultz KE, Krishna Narla R, Peng X, Tran T, Kulkarni A, Bahmanyar S, Condroski K, Pagarigan B, Fenalti G, LeBrun L, Leftheris K, Zhu D, Boylan JF.
Abstract: Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.
CiteXplore: 30998356
DOI: 10.1021/acs.jmedchem.8b01869
Patent ID: ┄