The Discovery of Orally Bioavailable Tyrosine Threonine Kinase (TTK) Inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as Anticancer Agents

  • J Med Chem. 2015 Apr 23;58(8):3366-92. doi: 10.1021/jm501740a.
Yong Liu  1 ,  Yunhui Lang  1 ,  Narendra Kumar Patel  1 ,  Grace Ng  1 ,  Radoslaw Laufer  1 ,  Sze-Wan Li  1 ,  Louise Edwards  1 ,  Bryan Forrest  1 ,  Peter B Sampson  1 ,  Miklos Feher  1 ,  Fuqiang Ban  1 ,  Donald E Awrey  1 ,  Irina Beletskaya  1 ,  Guodong Mao  1 ,  Richard Hodgson  1 ,  Olga Plotnikova  1 ,  Wei Qiu  2 ,  Nickolay Y Chirgadze  2 ,  Jacqueline M Mason  1 ,  Xin Wei  1 ,  Dan Chi-Chia Lin  1 ,  Yi Che  1 ,  Reza Kiarash  1 ,  Brian Madeira  1 ,  Graham C Fletcher  1 ,  Tak W Mak  1 ,  Mark R Bray  1 ,  Henry W Pauls  1
Affiliations
  • 1. †Campbell Family Institute for Breast Cancer Research, University Health Network, TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
  • 2. ‡Campbell Family Cancer Research Institute, University Health Network, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada.
PMID: 25763473 DOI: 10.1021/jm501740a
Abstract

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.

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