Design, synthesis and biological evaluation of novel HIF-1α PROTACs degrader as potent anti-cervical cancer agents.

Cervical cancer is the fourth most common and deadly cancer globally. Hypoxia-inducible factor-1α (HIF-1α) plays a key promoter of tumor progression and treatment resistance, making it an important anticancer target. Here, we designed and synthesized a series of novel HIF-1α-targeting PROTAC degraders based on LW-6 and its derivative W-1. Among them, Z12 showed the strongest anti-proliferative and HIF1α degradation activities in HeLa cells. Z12 promoted HIF-1α degradation via the ubiquitin-proteasome pathway by facilitating the formation of a HIF-1α/VHL ternary complex. Furthermore, Z12 inhibited HeLa cell proliferation, migration, and colony formation, induced apoptosis, and reduced p-MEK and p-AKT expression in the MAPK and PI3K/AKT pathways. This work offers a promising strategy for developing HIF1α-PROTAC degraders and treating cervical cancer.