2. Academic Validation
  3. Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent

Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer Agent

  • ACS Med Chem Lett. 2016 May 6;7(7):671-5. doi: 10.1021/acsmedchemlett.5b00485.
Yong Liu 1,  Radoslaw Laufer 1,  Narendra Kumar Patel 1,  Grace Ng 1,  Peter B Sampson 1,  Sze-Wan Li 1,  Yunhui Lang 1,  Miklos Feher 1,  Richard Brokx 1,  Irina Beletskaya 1,  Richard Hodgson 1,  Olga Plotnikova 1,  Donald E Awrey 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,  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 Center, 610 University Avenue, Toronto, Ontario M5G 2C4, Canada.
PMID: 27437075 DOI: 10.1021/acsmedchemlett.5b00485
Abstract

This work describes a scaffold hopping exercise that begins with known imidazo[1,2-a]pyrazines, briefly explores pyrazolo[1,5-a][1,3,5]triazines, and ultimately yields pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors. An X-ray structure of a representative compound is consistent with 1(1)/2 type inhibition and provides structural insight to aid subsequent optimization of in vitro activity and physicochemical and pharmacokinetic properties. Incorporation of polar moieties in the hydrophobic and solvent accessible regions modulates physicochemical properties while maintaining potency. Compounds with enhanced oral exposure were identified for xenograft studies. The work culminates in the identification of a potent (TTK K i = 0.1 nM), highly selective, orally bioavailable Anticancer agent (CFI-402257) for IND enabling studies.

Keywords

11/2 type inhibitors; CFI-402257; TTK inhibitors; pyrazolo[1,5-a]pyrimidines.

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