Targeting transcription factors through an IMiD independent zinc finger domain

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

doi:10.1038/s44321-025-00241-3

Targeting transcription factors through an IMiD independent zinc finger domain

Journal Article · Wed May 14 00:00:00 EDT 2025 · EMBO Molecular Medicine (Online)

DOI:https://doi.org/10.1038/s44321-025-00241-3· OSTI ID:2566293

Liu, Bee Hui; ; Radhakrishnan, Sridhar; Dai, Meng-Yuan; ; ; Tang, Jing Ping; ; Go, Mei Lin; Vu, Kim Anh L.; Kwon, Junsu; ; ; Tian, Xi; Feng, Li; ; Melkonian, Arek V.; Liu, Zhaoji; Wulf, Gerburg; Arthanari, Haribabu more »

Abstract

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.

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Sponsoring Organization:: USDOE

OSTI ID:: 2566293

Journal Information:: EMBO Molecular Medicine (Online), Journal Name: EMBO Molecular Medicine (Online); ISSN 1757-4684

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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