Liu Yong, Lang Yunhui, Patel Narendra Kumar, Ng Grace, Laufer Radoslaw, Li Sze-Wan, Edwards Louise, Forrest Bryan, Sampson Peter B, Feher Miklos, Ban Fuqiang, Awrey Donald E, Beletskaya Irina, Mao Guodong, Hodgson Richard, Plotnikova Olga, Qiu Wei, Chirgadze Nickolay Y, Mason Jacqueline M, Wei Xin, Lin Dan Chi-Chia, Che Yi, Kiarash Reza, Madeira Brian, Fletcher Graham C, Mak Tak W, Bray Mark R, Pauls Henry W
†Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
‡Campbell Family Cancer Research Institute, University Health Network, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada.
J Med Chem. 2015 Apr 23;58(8):3366-92. doi: 10.1021/jm501740a. Epub 2015 Apr 3.
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 (T(1/2) > 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.
乙酰氨基和甲酰胺基取代的3-(1H-吲唑-3-基)苯磺酰胺是有效的TTK抑制剂。然而，它们在减弱癌细胞生长方面能力有限；其物理化学性质以及随之而来的药代动力学参数并不具备药物样特性。通过去除极性的3-磺酰胺基团并在苯环的4位接上一个杂环，获得了具有口服暴露活性的强效抑制剂。一个X射线共晶体结构和一个优化的结合模型使得能够采用结构导向方法。系统优化产生了新型的TTK抑制剂，即3-(4-(杂环基)苯基)-1H-吲唑-5-甲酰胺。包含3-羟基-8-氮杂双环[3.2.1]辛烷-8-基双环系统的化合物具有强效（TTK IC50 <10 nM，HCT116 GI50 <0.1 μM），显示出低脱靶活性（>500倍）和微粒体稳定性（T(1/2)>30分钟）。在啮齿动物药代动力学和人类癌症小鼠异种移植模型中测试了一个子集化合物。化合物75（CFI-401870）重现了TTK RNA干扰的表型，口服给药后显示出体内肿瘤生长抑制作用，并被选用于临床前评估。
