Identification of a Potent and Selective CDK9 Degrader as a Targeted Therapeutic Option for the Treatment of Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) represents a significant public health challenge due to its increasing incidence and high mortality. Most SCLC patients are diagnosed at advanced stages, and there are limited effective targeted therapies available. In this study, a potent and selective CDK9 degrader, C3, was developed through PROTAC modification of the CDK9 inhibitor, AT-7519. C3 effectively induced apoptosis in various SCLC cell lines at low nanomolar concentrations and demonstrated favorable in vivo tolerance and adequate oral bioavailability. Notably, PROTAC C3 significantly reduced the proliferation of primary tumor samples from patients in mini-PDX models. Our findings indicate that the targeted degradation of CDK9 could become a viable strategy for treating SCLC, highlighting its potential therapeutic value. Additionally, this research offers a general structural optimization and evaluation strategy to improve the degradative selectivity, metabolic stability, and oral availability of PROTAC molecules.