Targeting transcription factors through an IMiD independent zinc finger domain
Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in three clusters, including an IMiD degron in zinc finger cluster one (ZFC1). Surprisingly, IMiDs do not inhibit the growth of SALL4-expressing cancer cells. To overcome this limit, we focused on a non-IMiD domain, SALL4 zinc finger cluster four (ZFC4). By combining ZFC4-DNA crystal structure and an in silico docking algorithm, in conjunction with cell viability assays, we screened several chemical libraries against a potentially druggable binding pocket, leading to the discovery of SH6, a compound that selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 treatment led to a significant 87% tumor growth inhibition of SALL4+ patient-derived xenografts and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors such as SALL4 in cancer.
Authors
- Kotni Meena Kumari
- Justin L. Tan (ORCID: https://orcid.org/0000-0003-0268-7363)
- J. Sivaraman (ORCID: https://orcid.org/0000-0001-9781-5326)
- Kijun Song (ORCID: https://orcid.org/0000-0002-6037-9345)
- Gerburg M. Wulf (ORCID: https://orcid.org/0000-0001-7868-6231)
- Yeu Khai Choong (ORCID: https://orcid.org/0000-0002-2868-3929)
- Hao Fan (ORCID: https://orcid.org/0000-0003-0199-9752)
- Mei‐Lin Go (ORCID: https://orcid.org/0000-0003-4757-3343)
- Arek V. Melkonian (ORCID: https://orcid.org/0009-0000-7804-647X)
- Bee Hui Liu
- Haribabu Arthanari (ORCID: https://orcid.org/0000-0002-7281-1289)
- R. Sridhar (ORCID: https://orcid.org/0000-0002-5068-3175)
- Sirano Dhe‐Paganon (ORCID: https://orcid.org/0000-0003-0824-5929)
- John G. Clohessy (ORCID: https://orcid.org/0000-0001-5186-9775)
- Daniel G. Tenen (ORCID: https://orcid.org/0000-0002-6423-3888)
- Li Chai (ORCID: https://orcid.org/0000-0003-1937-4750)
- Zhaoji Liu
- Xi Tian (ORCID: https://orcid.org/0000-0003-1965-0647)
- Hyuk‐Soo Seo (ORCID: https://orcid.org/0000-0003-0646-2102)
- Jun Qi (ORCID: https://orcid.org/0000-0002-1461-3356)
- Jing Tang (ORCID: https://orcid.org/0000-0001-7480-7710)
- Chaitanya K. Jaladanki (ORCID: https://orcid.org/0000-0001-5222-1137)
- Junsu Kwon (ORCID: https://orcid.org/0000-0002-6187-1366)
- Kim Anh L. Vu
- Miao Liu (ORCID: https://orcid.org/0000-0003-3365-0213)
- Feng Li (ORCID: https://orcid.org/0000-0002-0646-6560)
- Chong Gao (ORCID: https://orcid.org/0000-0002-8934-1586)
- Mengyuan Dai
Institutions
- Agency for Science, Technology and Research (SG)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- National University of Singapore (SG)
- Wuhan University (CN)
- Shenzhen Bay Laboratory (CN)
- National University Cancer Institute, Singapore (SG)
- Dana-Farber Cancer Institute (US)
- Zhongnan Hospital of Wuhan University (CN)
- Duke-NUS Medical School (SG)
- Harvard Stem Cell Institute (US)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s44321-025-00241-3
- Citations
- 3
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Foundation for the National Institutes of Health
- Breast Cancer Research Foundation
- Ministry of Health -Singapore
- National Research Foundation Singapore
- Ministry of Education - Singapore
- Argonne National Laboratory