Lead Optimization of an Aminopyrazole Scaffold to EXEL-1855, a Highly Selective PLK4 Inhibitor with Potent Antitumor Efficacy
Ryan L. Gonciarz, Trevor Chang, Andre H. St. Amant, Joon Won Jeong, Danny Ng, Nigam M. Mishra, Sanjay Bhattarai, Justin M. Salvant, Jo-Ting Chang, Faming Jiang, Halesha Basavarajappa, Ziqiang Wang, David Cole, Huy H. Nguyen, Jae H. Chang, Aditya Kumar, Leo Mok, Wei Xu, John M. Sanders, Deepak Gurbani, Dana M. Gwinn, Brian A. Sherer, Nina M. Muñoz, Christopher Kochansky, Jeremy M. Murray, Heather J. FinlayAbstract
Polo-like kinase 4 (PLK4) is a serine/threonine kinase that has an essential role in regulating centriole duplication and centrosome biogenesis during cell-cycle progression and a potential therapeutic target in various human cancers. Structure-guided lead optimization of an aminopyrazole scaffold at three key vectors led to the identification of EXEL-1855, which demonstrated a significant improvement in cellular potency, increased selectivity over related-kinases and an improved pharmacokinetic profile. Targeting the non-conserved Met91 residue in the PLK4 lower hinge region and optimizing this interaction, enabled EXEL-1855 to be most selective PLK4 inhibitor reported to date. In a preclinical CHP-134 neuroblastoma mouse xenograft model, EXEL-1855 showed robust efficacy and was well-tolerated at all dose levels. Taken together, our medicinal chemistry campaign resulted in a highly optimized, orally bioavailable, and efficacious inhibitor of PLK4, with the potential to advance as an oral single-agent for the treatment of neuroblastoma with a projected human dose of 540 mg QD.