Bifunctional compounds for targeted degradation of carbonic anhydrase IX through integrin-facilitated lysosome degradation
As an important therapeutic target, carbonic anhydrase IX (CAIX) is crucial in the pH regulation of hypoxic solid tumors, thus keeping the survival of them in acidic microenvironment and promoting their proliferation, invasion, and metastasis. To degrade endogenous CAIX, three bifunctional compounds were designed according to the integrin-facilitated lysosomal degradation strategy. These compounds are composed of a CAIX-binding ligand, an integrin-recognizing ligand, connected via a linker, which could induce CAIX degradation in an integrin- and lysosome-dependent manner. Among them, Sul-L1-RGD showed the highest degradation efficacy and could inhibit the proliferation of tumor cells under hypoxic conditions, thus it has great potential to be applied in cancer drug discovery.
Authors
- Joong Sup Shim (ORCID: https://orcid.org/0000-0003-0167-7307)
- Jiwei Zheng (ORCID: https://orcid.org/0000-0002-3180-0612)
- Lijing Fang (ORCID: https://orcid.org/0000-0001-7355-3923)
- Hang Fai Kwok (ORCID: https://orcid.org/0000-0002-6349-4517)
- Mengyu Yao
- Ruihang Cai (ORCID: https://orcid.org/0000-0002-4283-2222)
- Congli Chen (ORCID: https://orcid.org/0009-0001-0997-0682)
- Liang Chen (ORCID: https://orcid.org/0000-0002-4875-5811)
- Xiaojun Yao (ORCID: https://orcid.org/0000-0002-6972-2971)
- Wanyi He (ORCID: https://orcid.org/0009-0003-8779-1932)
Institutions
- Chinese Academy of Sciences (CN)
- University of Macau (MO)
- Shenzhen Institutes of Advanced Technology (CN)
- Macao Polytechnic University (MO)
Publication Details
- Journal
- Journal of Biological Chemistry
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1016/j.jbc.2025.108482
- Citations
- 1
- Primary Topic
- Enzyme function and inhibition
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Science, Technology and Innovation Commission of Shenzhen Municipality
- National Key Research and Development Program of China