Discovery of Pyrazolo[1,5-a]pyrimidine TTK Inhibitors: CFI-402257 is a Potent, Selective, Bioavailable Anticancer
Yong Liu1, Radoslaw Laufer1, Narendra Kumar Patel1
1Campbell Family Institute for Breast Cancer Research, University Health Network , TMDT East Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
ACS Medicinal Chemistry Letters
|July 21, 2016
Summary
Researchers identified novel pyrazolo[1,5-a]pyrimidines as potent TTK inhibitors. This led to the discovery of CFI-402257, a selective, orally bioavailable anticancer agent for further development.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Oncology
Background:
- Imidazo[1,2-a]pyrazines were known scaffolds for TTK inhibition.
- Targeting TTK is a strategy for cancer therapy.
Purpose of the Study:
- To discover novel potent TTK inhibitors through scaffold hopping.
- To identify an orally bioavailable anticancer agent for clinical development.
Main Methods:
- Scaffold hopping from imidazo[1,2-a]pyrazines to pyrazolo[1,5-a]pyrimidines.
- X-ray crystallography for structural insights.
- Optimization of in vitro activity, physicochemical, and pharmacokinetic properties.
Main Results:
- Identified pyrazolo[1,5-a]pyrimidines as a novel class of potent TTK inhibitors.
- Determined a representative compound's binding mode via X-ray crystallography.
- Optimized compounds for enhanced oral bioavailability and in vivo efficacy in xenograft models.
Conclusions:
- A potent (TTK Ki = 0.1 nM), selective, and orally bioavailable anticancer agent, CFI-402257, was identified.
- Structural insights guided optimization of drug-like properties.
- CFI-402257 is a promising candidate for Investigational New Drug (IND) enabling studies.
