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

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.