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

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.

PMID: 41307127
DOI: 10.3324/haematol.2025.288221

Free article

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

Amit K Jaiswal et al. Haematologica. 2025.

Free article

. 2025 Nov 27.

doi: 10.3324/haematol.2025.288221. Online ahead of print.

Authors

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.

PMID: 41307127
DOI: 10.3324/haematol.2025.288221

Abstract

The RNA-binding protein IGF2BP3 is an oncofetal protein overexpressed in B-acute lymphoblastic leukemia and is critical for leukemogenesis in experimental models. With cancerspecific expression, functional dispensability for normal development, and an unleveraged prooncogenic function in mRNA homeostasis, IGF2BP3 represents an excellent target. With no small molecule inhibitors of IGF2BP3 in clinical use, we undertook an effort 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 mRNAs, 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.

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

Affiliations

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

Authors

Affiliations

Abstract

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