A small molecule inhibitor of RNA-binding protein IGF2BP3 shows anti-leukemic activity

Year: 2025

Type: article

Abstract: The RNA-binding protein IGF2BP3 is an oncofetal protein over-expressed in B-cell acute lymphoblastic leukemia and is critical for leukemogenesis in experimental models. With cancer-specific expression, functional dispensability for normal development, and an unleveraged pro-oncogenic function in mRNA homeostasis, IGF2BP3 represents an excellent target. With no small molecule inhibitors of IGF2BP3 in clinical use, we aimed to identify new IGF2BP3 inhibitors using biochemical methods. A biochemical screen, followed by a cell-based counter screen led to the identification of compounds with protein-RNA interaction inhibition and leukemic cell growth-inhibitory activity. One of these compounds, designated I3IN-002, shows consistent cell growth-inhibitory activity, altered cell cycle, and increased apoptosis in multiple leukemia cell lines, and is the most potent inhibitor of IGF2BP3 reported to date. I3IN-002 was tolerated in mice when administered intraperitoneally and showed potent anti-leukemic activity in a syngeneic transplantation model of MLL-Af4 leukemia. I3IN-002 inhibits the function of IGF2BP3, disrupting in situ binding of IGF2BP3 to target mRNA, and altering IGF2BP3-dependent gene expression regulation. Furthermore, cell-free and cellular thermal shift assays, as well as drug affinity responsive target stability assays support on-target activity of I3IN-002 for IGF2BP3. Thus, the identification of I3IN-002 paves the way for the discovery of potent and selective small molecule inhibitors of IGF2BP3.

Source: Haematologica

DOI: 10.3324/haematol.2025.288221

Authors: Amit K Jaiswal, Georgia M Scherer, Michelle L Thaxton, Jacob P Sorrentino, Constance Yuen, Milauni M Mehta, Gunjan Sharma, Tasha L Lin, Tiffany M Tran, Amanda Cohen, Alexander J Ritter, Rishi S Kotecha, Jeremy R Sanford, Robert D Damoiseaux, Neil K Garg, Dinesh S Rao

Institutions: University of California, Los Angeles, California NanoSystems Institute, University of California, Santa Cruz, The Kids Research Institute Australia, The University of Western Australia, Curtin University, Princess Margaret Hospital for Children, Perth Children's Hospital

Language: English

Topic: Acute Lymphoblastic Leukemia research

Subfield: Public Health, Environmental and Occupational Health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,157

Funders: National Science Foundation, California Institute for Regenerative Medicine, California Institute of Regenerative Medicine, National Institutes of Health, Center for AIDS Research, University of Washington, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Center for Research Resources, Division of Chemistry, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, UCLA AIDS Institute, Office of Research Infrastructure Programs, National Institutes of Health

OpenAlex ID: W4416767684