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

  • Nat Commun. 2026 Mar 25. doi: 10.1038/s41467-026-70663-1.
Monica C Rodrigo-Brenni  1 ,  Jasper C Komen  1 ,  Ghaith M Hamza  2 ,  Natacha Bohin  1 ,  Tomas Adomavicius  3 ,  Angelo Andres  2 ,  Stefan Blaho  4 ,  Ulf Börjesson  5 ,  Gavin W Collie  3 ,  Gian Marco De Donatis  6 ,  Frederik Eisele  7 ,  Ning Gao  2 ,  Andrea Gohlke  3 ,  Christoph Grebner  5 ,  Frida Gustafsson  1 ,  Andreas Hock  6 ,  Cecilia Kankkonen  7 ,  Praveen Kumar  8 ,  Emilyanne Leonard  9 ,  Xin Li  10 ,  Ruth Macdonald  11 ,  Katja Madeyski-Bengtson  12 ,  Eric Miele  2 ,  Philip Nevin  7 ,  Jeroen Overman  6 ,  Fiona Pachl  2 ,  Claudio Pathe  6 ,  Matthew W D Perry  13 ,  Christopher Phillips  3 ,  Andy Pike  14 ,  Ian Purvis  11 ,  Timothy Rasmusson  2 ,  Sophie Regan  1 ,  Linda Reilly  1 ,  Jonathan Rose  11 ,  R Ian Storer  15 ,  Jingwen Wang  10 ,  Xiang Zhai  2 ,  Iacovos N Michaelides  16 ,  Kevin Moreau  17
Affiliations
  • 1. Safety Sciences, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 2. Assays, Profiling & Cell Sciences, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA.
  • 3. Protein, structure and biophysics, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 4. Protein, structure and biophysics, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 5. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 6. Assays, Profiling & Cell Sciences, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 7. Assays, Profiling & Cell Sciences, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
  • 8. Data Sciences & Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Boston, MA, USA.
  • 9. Integrated Bioanalysis, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 10. Pharmaron Beijing Co., Ltd, 100176, Beijing, People's Republic of China.
  • 11. Animal Science & Technologies, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 12. Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • 13. Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuicals R&D, AstraZeneca, Gothenburg, Sweden.
  • 14. DMPK, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 15. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK.
  • 16. Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK. [email protected].
  • 17. Safety Sciences, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK. [email protected].
PMID: 41876537 DOI: 10.1038/s41467-026-70663-1
Abstract

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.

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