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

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

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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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-116190
    TKK Inhibitor