PSP-0119: Targeted IRAK4 Degradation as a Novel Therapeutic Strategy for FLT3-Mutant AML

  • bioRxiv. 2025 Oct 2:2025.09.30.679569. doi: 10.1101/2025.09.30.679569.
Negar Khazan  1 ,  Cameron Wa Snyder  1 ,  Chandhana Ravi  1 ,  Elizabeth Lamere  2 ,  Niloy A Singh  1  2 ,  Manoj K Khera  3 ,  Jane Liesveld  2 ,  Srinivasan Ekambaram  4 ,  Nikolay V Dokholyan  4  5  6 ,  Myla Strawderman  7 ,  Kyu Kwang Kim  1 ,  Rachael Rowswell-Turner  1 ,  Michael W Becker  2 ,  Richard G Moore  1 ,  Rakesh K Singh  1
Affiliations
  • 1. Department of Gynecologic Oncology, University of Rochester Medical Center, Rochester, NY, 14642.
  • 2. Department of Medicine, University of Rochester Medical Center, Rochester, NY, 14642.
  • 3. Presude Lifesciences Private Limited, Delhi, India.
  • 4. Department of Neurology, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA.
  • 5. Department of Neuroscience, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA.
  • 6. Department of Biomedical Engineering, University of Virginia, School of Medicine, Charlottesville, VA 22903, USA.
  • 7. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, 14642.
PMID: 41256437 DOI: 10.1101/2025.09.30.679569
Abstract

Acute Myeloid Leukemia (AML) is a life-threatening hematologic malignancy. Despite recent therapeutic advances, rising incidence rates emphasize the urgent need for identification of new targets and therapies. Roles of interleukin receptor-associated kinases IRAK1/4 are emerging in hematologic and solid malignancies. In AML, IRAK4 mRNA is overexpressed at diagnosis, relapses, in residual disease, and in FLT3-ITD-mutant cells, MDS, MPN, and MDS/MPN-negative subtypes. Compared with hematopoietic stem cells, IRAK4 is elevated in t(15;17), inv(16)/t(16;16), and t(11q23)/MLL subtypes, correlating with poor survival. Here, we disclose anti-AML activity of PSP-0119, a novel IRAK4 PROTAC degrader. PSP-0119, inhibited IRAK4 kinase activity, NF-κβ activity, and IL-1β-induced IRAK4 phosphorylation. In-silico docking revealed interactions in CRBN/IRAK4/PSP-0119 ternary complex. PSP-0119 degraded IRAK4 in FLT3-mutant AML cell lines sparing FLT3-wild-type AML cells, FLT3-wild-type patient samples, and normal bone-marrow. Bulk-seq of PSP-0119 treated MOLM-13 cells revealed downregulation of eNOS, a poor AML prognosticator. PSP-0119 suppressed colony formation, cell viability, and MOLM-13 xenograft growth, and synergized with IRAK1 covalent inhibitor JH-X-119-01. PSP-0119 is metabolically stable, retaining 71% of parent compound at 60 minutes in human liver microsomes. In summary, IRAK4 degradation via PSP-0119 as a promising therapeutic strategy for treatment of FLT3-mutant AML.

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