Preclinical study demonstrates potent antiproliferative efficacy of novel indolin-2-one PLK4 inhibitors in tumor xenografts, suggesting therapeutic potential for targeted cancer therapy.
Key Points
To identify, design, and optimize potent and selective small-molecule inhibitors of polo-like kinase 4 (PLK4) as novel antiproliferative cancer therapeutics.
Initiated lead generation through directed virtual screening using a ligand-based focused library and a PLK4 homology model.
Optimized hit structures into novel (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one analogs guided by published PLK4 kinase domain X-ray crystallographic models.
Characterized kinase selectivity profiles, cell cycle effects in vitro, and antitumor efficacy in vivo using a xenograft model with optimized compound 50 (CFI-400437).
Generated optimized (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one compounds exhibiting nanomolar inhibitory potency against PLK4.
Demonstrated marked antiproliferative activity and disruption of the cell cycle alongside a favorable kinase selectivity profile.
Achieved significant in vivo tumor growth inhibition in animal xenograft studies administered the lead candidate CFI-400437.