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<p>Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). When these IMiD scaffolds are integrated into proteolysis targeting chimeras (PROTACs), they can inadvertently lead to the degradation of these neosubstrates alongside the intended protein of interest (POI), raising safety concerns. This study profiles existing PROTACs and reveals instances of undesired degradation of IMiD-associated neosubstrates. We have developed in vitro hematopoietic assays to scrutinize the IMiD effects and describe the mechanistic insights on cell differentiation rewiring towards megakaryocytes together with an activation of the interferon response that is phenocopied by an Ikaros knock-out model. Moreover, we have identified a CRBN ligand that mitigates these safety liabilities and can be effectively incorporated into PROTACs. This advancement provides a promising path toward safer preclinical development of PROTACs, especially as the field expands into chronic disease treatments beyond oncology.</p>

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A dihydrouracil CRBN ligand mitigates IMiD associated safety liabilities in heterobifunctional targeted protein degrader

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月25日

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  • Monica C. Rodrigo-Brenni,
  • Jasper C. Komen,
  • Ghaith M. Hamza,
  • Natacha Bohin,
  • Tomas Adomavicius,
  • Angelo Andres,
  • Stefan Blaho,
  • Ulf Börjesson,
  • Gavin W. Collie,
  • Gian Marco De Donatis,
  • Frederik Eisele,
  • Ning Gao,
  • Andrea Gohlke,
  • Christoph Grebner,
  • Frida Gustafsson,
  • Andreas Hock,
  • Cecilia Kankkonen,
  • Praveen Kumar,
  • Emilyanne Leonard,
  • Xin Li,
  • Ruth Macdonald,
  • Katja Madeyski-Bengtson,
  • Eric Miele,
  • Philip Nevin,
  • Jeroen Overman,
  • Fiona Pachl,
  • Claudio Pathe,
  • Matthew W. D. Perry,
  • Christopher Phillips,
  • Andy Pike,
  • Ian Purvis,
  • Timothy Rasmusson,
  • Sophie Regan,
  • Linda Reilly,
  • Jonathan Rose,
  • R. Ian Storer,
  • Jingwen Wang,
  • Xiang Zhai,
  • Iacovos N. Michaelides,
  • Kevin Moreau

摘要

Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are effective in treating multiple myeloma (MM) but pose hematotoxicity risks by degrading neosubstrates Ikaros (IKZF1) and Aiolos (IKZF3). When these IMiD scaffolds are integrated into proteolysis targeting chimeras (PROTACs), they can inadvertently lead to the degradation of these neosubstrates alongside the intended protein of interest (POI), raising safety concerns. This study profiles existing PROTACs and reveals instances of undesired degradation of IMiD-associated neosubstrates. We have developed in vitro hematopoietic assays to scrutinize the IMiD effects and describe the mechanistic insights on cell differentiation rewiring towards megakaryocytes together with an activation of the interferon response that is phenocopied by an Ikaros knock-out model. Moreover, we have identified a CRBN ligand that mitigates these safety liabilities and can be effectively incorporated into PROTACs. This advancement provides a promising path toward safer preclinical development of PROTACs, especially as the field expands into chronic disease treatments beyond oncology.