CDK9 targeting PROTAC L055 inhibits ERα-positive breast cancer

Breast cancer is one of the most prevalent malignancies affecting women worldwide, underscoring the urgent need for more effective and specific treatments. Proteolysis-targeting chimeras (PROTACs) have emerged as a promising strategy to develop new lead compounds by selectively targeting oncoproteins for degradation. In this study, we designed, synthesized and evaluated a CRBN-based PROTAC, L055, which targets CDK9. Our findings demonstrate that L055 effectively inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells in vitro. L055 specifically binds to CDK9, facilitating its degradation via the CRBN-dependent proteasomal pathway. Additionally, L055 suppressed the growth of organoids and tumors derived from T47D and MCF7 cells in nude mice. Thus, L055 represents a potential novel therapeutic agent for ERα-positive breast cancer and potentially other malignancies. CRBN-based PROTAC L055 inhibits ERα-positive breast cancer partially through degrade CDK9 and decrease downstream target genes' expression. • CRBN-based PROTAC, L055 inhibits the proliferation, induces cell cycle arrest, and decreases the survival of ERα-positive breast cancer cells. • L055 suppressed the growth of organoids and tumors. • L055 binds to CDK9, facilitates CDK9 degradation via the CRBN-dependent proteasomal pathway. • L055 represents a potential novel therapeutic agent for ERα-positive breast cancer.