Identification of an allosteric site on the E3 ligase adapter cereblon

  • Nature. 2026 Mar;651(8105):482-490. doi: 10.1038/s41586-025-09994-w.
Vanessa N Dippon  1 ,  Zeba Rizvi  #  2 ,  Anthony E Choudhry  #  3 ,  Chun-Wa Chung  4 ,  Ibrahim F Alkuraya  1 ,  Wenqing Xu  1 ,  Xavier B Tao  1 ,  Anthony J Jurewicz  3 ,  Jessica L Schneck  3 ,  Wenqian Chen  2  5 ,  Nicole M Curnutt  1 ,  Farah Kabir  1 ,  Kwok-Ho Chan  4 ,  Markus A Queisser  4 ,  Caterina Musetti  3  6 ,  Han Dai  3 ,  Gabriel C Lander  2 ,  Andrew B Benowitz  7 ,  Christina M Woo  8  9
Affiliations
  • 1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  • 2. Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.
  • 3. GSK, Research Technologies, Collegeville, PA, USA.
  • 4. GSK, Research Technologies, Stevenage, UK.
  • 5. Genentech, South San Francisco, CA, USA.
  • 6. Bristol Myers Squibb, Lawrenceville, NJ, USA.
  • 7. GSK, Research Technologies, Collegeville, PA, USA. [email protected].
  • 8. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. [email protected].
  • 9. Broad Institute, Cambridge, MA, USA. [email protected].
  • # Contributed equally.
PMID: 41565821 DOI: 10.1038/s41586-025-09994-w
Abstract

Cereblon (CRBN) is the target of thalidomide derivatives1 that achieve therapeutic efficacy against some haematologic neoplasias2-4 by recruiting neosubstrates for degradation5-7. Despite the intense investigation of orthosteric thalidomide derivatives, little is known about alternate binding sites on CRBN. Here we report an evolutionarily conserved cryptic allosteric binding site on CRBN. Small-molecule SB-405483 binds the allosteric site to cooperatively enhance the binding of orthosteric ligands and alter their neosubstrate degradation profiles. A survey of over 100 orthosteric ligands and their degradation targets reveals trends in the classes of compounds and neosubstrates in which degradation outcomes are enhanced or inhibited by SB-405483. Structural investigations provide a mechanistic basis for the effects of the allosteric ligand by shifting the conformational distribution of CRBNopen to a novel CRBNint and increasing the CRBNclosed state. The discovery of a cryptic allosteric binding site on CRBN that alters the functional effects of orthosteric ligands opens new directions with broad implications for improving the selectivity and efficacy of CRBN therapeutics.

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