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.
Authors
Funding
China Academy of Chinese Medical Sciences Institute of Chinese Materia Medica Grant 037GJHZ2023043FNChinese Academy of Sciences FundingScience and Technology Program of Gansu Province Grant 24RCKA007Science and Technology Program of Gansu Province Grant 23JRRA623Science and Technology Program of Gansu Province Grant 23ZDNA002Science and Technology Program of Gansu Province Grant 23ZYQK0001