2. Academic Validation
  3. Pharmacological targeting of IRF4 as a therapeutic strategy for multiple myeloma

Pharmacological targeting of IRF4 as a therapeutic strategy for multiple myeloma

  • Nat Chem Biol. 2026 May 28. doi: 10.1038/s41589-026-02228-8.
Michael P Agius # 1 2,  Chen Song # 2 3,  Qi Liu 2 3,  Tomoki Iemura 1 2,  Laura Hevenor 1 2,  N Connor Payne 4 5 6,  Romanos Sklavenitis Pistofidis 1 2,  Lorena Pantano 1 2,  Hongfang Zhao 2 3,  Hyuk-Soo Seo 7 8,  Daniel Heilpern-Mallory 1 2,  Caleb Heaslip 2 3,  Zhen-Yu J Sun 3,  Puspalata Bashyal 1 2,  Michelle P Aranha 1 2,  Elizabeth Lightbody 1 2,  Ralph Mazitschek 4 6 9,  Sirano Dhe-Paganon 7 8,  Constantine S Mitsiades 1 2,  Irene M Ghobrial 10 11,  Jun Qi 12 13
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 2 Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 4 Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
  • 5 Harvard Department of Chemistry and Chemical Biology, Cambridge, MA, USA.
  • 6 Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • 7 Chemical Biology Program, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 8 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 9 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 10 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 11 Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • 12 Department of Medicine, Harvard Medical School, Boston, MA, USA. [email protected].
  • 13 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • # Contributed equally.
PMID: 42209806 DOI: 10.1038/s41589-026-02228-8
Abstract

Interferon regulatory factor 4 (IRF4) is an oncogenic transcription factor (TF) in several hematological malignancies. To date, no pharmacological agents have been developed specifically for IRF4 due to the challenging nature of targeting TFs. Here we first identified (S)-H1, a binder of IRF4, by targeting the SPI1-IRF4 interaction on IRF4's interferon association domain via high-throughput screening. Next, we successfully turned our binder into dIRF4-2, a first-in-class proteolysis-targeting chimera of IRF4, by linking (S)-H1 to E3 Ligase ligands of Cereblon. dIRF4-2 can induce highly selective proteasomal degradation of IRF4 and has strong cytotoxic effects in all multiple myeloma lines evaluated in vitro. Our study showcases methodology to effectively target the IRF family of TFs and illustrates how to convert an inert binder into a powerful chemical probe for studying the functions of important oncoproteins that are structurally difficult to target.

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