Discovery of rigid linker-based CDK4/6 PROTACs for the treatment of breast cancer.
Selective cyclin-dependent kinase (CDK) 4/6 inhibitors play a leading role in the treatment of breast cancer; however, their efficacy is often limited by acquired resistance. Proteolysis-targeting chimera (PROTAC) technology has recently emerged as a promising therapeutic strategy to overcome drug resistance. In this study, we designed and synthesized a series of novel CDK4/6 PROTACs based on dalpiciclib incorporating rigid linkers. The optimal compound P11 exhibited potent and selective CDK4/6 degradation activity mediated by the ubiquitin-proteasome system. Binding model analysis demonstrated that P11 is capable of forming a stable CDK6-CRBN-P11 ternary complex. P11 significantly inhibited proliferation and colony formation, and induced cell cycle arrest in breast cancer cell lines. Furthermore, P11 effectively suppressed tumor growth in an MCF-7 xenograft model, demonstrating stronger anti-breast cancer activity than dalpiciclib both in vitro and in vivo. Importantly, P11 showed potential to overcome acquired resistance to CDK4/6 inhibitors. Therefore, P11 could be a promising preclinical candidate for further development.