Discovery of a “First-in-Class” Selective Multikinase (CDK4/6/9-AURKA/B) Inhibitor, LCI133, for Neuroblastoma

Our central hypothesis in this report is that the development of a single small molecule inhibitor that binds to multiple targets will be safer and more efficacious against high-risk cancers which rapidly develop resistance to one targeted therapeutic agent. We used a rational pharmacophore merging strategy and X-ray crystal structures of CDK6, CDK9, and AURKA to discover <b>LCI133</b>, a "first-in-class" nanomolar (nM) potent CDK4/6/9-AURKA/B inhibitor. Selectivity profiling of <b>LCI133</b> using the scanMAX kinome assay of 468 kinases revealed that it is highly selective for CDK4/9 and AURKA targets. Pharmacokinetic studies with <b>LCI133-HCl</b> in mice demonstrate a high systemic exposure (AUC) of 7812 ng × h/mL and maximum plasma concentration (<i>C</i>_max) of 3305 ng/mL. Neuroblastoma (NB) cells displayed nM sensitivity to <b>LCI133</b> in vitro, and we observed potent antitumor effects in vivo in a BE(2)-C neuroblastoma xenograft model, without overt toxicity and an increase in the overall survival rate.