Chemistry Department Seminar: PLK4 Inhibitor CFI-400945 as an Anticancer Agent -From Hits to Clinical Trial



Dr Yong Liu

Ontario Institute for Cancer Research, Toronto, Canada


Polo-like kinase 4 (PLK4), a unique member of the polo-like kinase family of serine-threonine kinases, is a master regulator of centriole duplication that is important for maintaining genome integrity. Overexpression of PLK4 is found in several human cancers and PLK4 was identified as a potential target for cancer therapy. This talk is about the discovery and the clinical trial of a PLK4 inhibitor, CFI-400945.

Earlier efforts to identify potent and efficacious PLK4 inhibitors resulted in the discovery of (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which are
superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones. The racemic cyclopropane-linked compounds showed PLK4
affinity and antiproliferative activity comparable to their alkene-linked congeners with improved physicochemical, ADME, and pharmacokinetic properties. 1R,2S enantiomer was preferred based on enzymatic and cellular activities. Further optimizations resulted in potent, selective and orally bioavailable PLK4 inhibitor CFI-400945. A stable formulation (fumurate) was development for first in man studies. IND and CTA filed and approved by FDA and Health Canada in 2014. CFI-400945 is currently undergoing phase I clinical trial studies treating patients with advanced solid tumors.