| Title: |
Targeting transcription factors through an IMiD independent zinc finger domain |
| Authors: |
Liu, Bee Hui; Liu, Miao; Radhakrishnan, Sridhar; Dai, Meng-Yuan; Jaladanki, Chaitanya Kumar; Gao, Chong; Tang, Jing Ping; Kumari, Kalpana; Go, Mei Lin; Vu, Kim Anh L; Kwon, Junsu; Seo, Hyuk-Soo; Song, Kijun; Tian, Xi; Feng, Li; Tan, Justin L; Melkonian, Arek V; Liu, Zhaoji; Wulf, Gerburg; Arthanari, Haribabu; Qi, Jun; Dhe-Paganon, Sirano; Clohessy, John G; Choong, Yeu Khai; Sivaraman, J; Fan, Hao; Tenen, Daniel G; Chai, Li |
| Contributors: |
Ministry of Health -Singapore; Ministry of Education - Singapore; National Research Foundation, Singapore; Foundation for the National Institutes of Health; DOE | SC | Argonne National Laboratory; Xiu Research Fund; Linde Family Foundation; AGA/Jenzabar Research Fund; Breast Cancer Research Foundation BCRF |
| Source: |
EMBO Molecular Medicine ; volume 17, issue 6, page 1393-1416 ; ISSN 1757-4684 |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2025 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s44321-025-00241-3 |
| Availability: |
https://doi.org/10.1038/s44321-025-00241-3; https://www.embopress.org/doi/epdf/10.1038/s44321-025-00241-3; https://www.embopress.org/doi/full/10.1038/s44321-025-00241-3 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.C8EE662B |
| Database: |
BASE |