LCI133

LCI133 is a novel, in silico-designed small molecule that functions as a triple inhibitor of Cyclin-dependent kinase 4/6 (CDK4/6), Cyclin-dependent kinase 9 (CDK9), and Aurora kinase A/B (AURKA/B). It is primarily being investigated for the treatment of endometrial cancer, particularly in tumors harboring PTEN loss-of-function mutations. The drug demonstrates nanomolar potency and induces selective, dose-dependent apoptosis in PTEN-mutant cell lines. Mechanistically, PTEN deficiency facilitates RNA Polymerase II-dependent transcriptional elongation, a process that LCI133 effectively inhibits, leading to a significant reduction in nascent RNA synthesis. Preclinical studies in xenograft models have shown that LCI133 significantly slows tumor growth in PTEN-knockdown environments while maintaining an acceptable safety profile.