Discovery of potent hypoxia-inducible factor-1α (HIF-1α) degraders by proteolysis targeting chimera (PROTAC).

Abstract

Under hypoxic conditions in tumor cells, HIF-1α is unable to bind to VHL E3 ligase due to the blocked hydroxylation reaction, resulting in impaired degradation and intracellular accumulation. Mounting evidences show a close association between HIF-1α overexpression and drug resistance, treatment failure, and increased mortality. To address HIF-1α overexpression, we innovatively introduced an E3 ligase ligand to the HIF-1α inhibitor IDF-11774 using the PROTACs strategy, aiming to reactivate the degradative pathway impeded under hypoxia, and thereby achieve the degradation of HIF-1α protein under hypoxia. Western blotting analyses demonstrated that most of our designed PROTACs effectively degraded HIF-1α. Among these, compounds C3 and V2 exhibited excellent anti-proliferation activity on MDA-MB-231 cells with IC₅₀ values of 48.98 μM and 7.54 μM, respectively. Both compounds induced protein degradation in a concentration-dependent manner, achieving degradation rates up to 80 %. Additionally, this degradation was inhibited by the proteasome inhibitor MG132. As a part of the ongoing effort to develop HIF-1 inhibitors, targeting the degradation of HIF-1α may offer an effective treatment strategy against solid tumors.