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

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

  • Bioorg Chem. 2024 Nov 4:153:107943. doi: 10.1016/j.bioorg.2024.107943.
Yuying Li 1,  Ruixue Zhu 2,  Xuelian He 2,  Yanjia Song 2,  Ting Fan 1,  Junhui Ma 2,  Guangya Xiang 3,  Xiang Ma 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 3 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Pharmacy, Tongren Polytechnic College, Tongren Guizhou 554300, China. Electronic address: youjiti@mails.tjmu.edu.cn.
  • 4 School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; School of Pharmacy, Tongren Polytechnic College, Tongren Guizhou 554300, China. Electronic address: xiangma@hust.edu.cn.
PMID: 39536629 DOI: 10.1016/j.bioorg.2024.107943
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.

Keywords

E3 ligase; HIF-1α; IDF-11774; PROTACs; Reactivated degradation.

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