Targeting transcription factors through an IMiD independent zinc finger domain

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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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Funding Information
  • Ministry of Health -Singapore (STaR18nov-0002)
  • Ministry of Education - Singapore
  • National Research Foundation Singapore (CIRG21nov-0009CIRG21nov-0009)
  • Foundation for the National Institutes of Health (P01HL131477-01A1)
  • Foundation for the National Institutes of Health (P01 HL158688/HL/NHLBI NIH)
  • Foundation for the National Institutes of Health (P30 GM124165)
  • Foundation for the National Institutes of Health (S10OD021527)
  • Argonne National Laboratory
  • Xiu research fund
  • Linde Family Foundation
  • AGA/Jenzabar Research Fund
  • Breast Cancer Research Foundation (24-177)

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