作者
Yong Liu,Yunhui Lang,Narendra Kumar Patel,Grace Ng,Radoslaw Laufer,Sze-Wan Li,Louise Edwards,Bryan Forrest,Peter B. Sampson,Miklós Fehér,Fuqiang Ban,Donald E. Awrey,Irina Beletskaya,Guodong Mao,Richard Hodgson,Olga Plotnikova,Wei Qiu,Nickolay Y. Chirgadze,Jacqueline M. Mason,Xin Wei,Dan Lin,Yi Che,Reza Kiarash,Brian Madeira,Graham C. Fletcher,Tak W. Mak,Mark R. Bray,Henry W. Pauls
摘要
The acetamido and carboxamido substituted 3-(1H-indazol-3-yl)benzenesulfonamides are potent TTK inhibitors. However, they display modest ability to attenuate cancer cell growth; their physicochemical properties, and attendant pharmacokinetic parameters, are not drug-like. By eliminating the polar 3-sulfonamide group and grafting a heterocycle at the 4 position of the phenyl ring, potent inhibitors with oral exposure were obtained. An X-ray cocrystal structure and a refined binding model allowed for a structure guided approach. Systematic optimization resulted in novel TTK inhibitors, namely 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides. Compounds incorporating the 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl bicyclic system were potent (TTK IC50 < 10 nM, HCT116 GI50 < 0.1 μM), displayed low off-target activity (>500×), and microsomal stability (T1/2 > 30 min). A subset was tested in rodent PK and mouse xenograft models of human cancer. Compound 75 (CFI-401870) recapitulated the phenotype of TTK RNAi, demonstrated in vivo tumor growth inhibition upon oral dosing, and was selected for preclinical evaluation.