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

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

doi:10.3324/haematol.2025.288221

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

Haematologica. 2026 Jun 1;111(6):1984-1998. doi: 10.3324/haematol.2025.288221. Epub 2025 Nov 27.

Authors

Amit K Jaiswal¹, Georgia M Scherer², Michelle L Thaxton¹, Jacob P Sorrentino², Constance Yuen³, Milauni M Mehta², Gunjan Sharma¹, Tasha L Lin¹, Tiffany M Tran¹, Amanda Cohen¹, Alexander J Ritter⁴, Rishi S Kotecha⁵, Jeremy R Sanford⁶, Robert D Damoiseaux⁷, Neil K Garg², Dinesh S Rao⁸

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA.
² Department of Chemistry and Biochemistry, University of California, Los Angeles, CA.
³ California Nanosystems Institute, University of California, Los Angeles, CA.
⁴ Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, CA.
⁵ Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Childrens Hospital, Perth, Australia; Leukemia Translational Research Laboratory, WA Kids Cancer Centre, University of Western Australia, Perth Australia; Curtin Medical School, Curtin University, Perth, Australia.
⁶ Department of Molecular, Cell and Developmental Biology and Center for Molecular Biology of RNA, University of California, Santa Cruz, CA, USA; Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA.
⁷ California Nanosystems Institute, University of California, Los Angeles, CA, USA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA; Department of Bioengineering, Samueli School of Engineering, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, CA.
⁸ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, CA, USA; Broad Stem Cell Research Center, University of California Los Angeles, CA. drao@mednet.ucla.edu.

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.

MeSH terms

Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Leukemia* / drug therapy
Leukemia* / metabolism
Leukemia* / pathology
Mice
RNA-Binding Proteins* / antagonists & inhibitors
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Small Molecule Libraries* / chemistry
Small Molecule Libraries* / pharmacology

Substances

RNA-Binding Proteins
Antineoplastic Agents
IGF2BP3 protein, human
Small Molecule Libraries