Small molecule discovery could open the door to new class of treatments for hard-to-treat cancers

They found that in leukemia cells that rely on IGF2BP3 for growth slowed dramatically when exposed to the molecule, while cells lacking the protein showed only a minimal response, a strong indication that the compound is acting on its intended target. In the treated IGF2BP3-positive cells, the molecule triggered apoptosis, or programmed cell death, and interfered with the protein's ability to bind RNA, a critical step in its tumor-promoting activity. It also reduced the expression of several cancer-promoting genes normally stabilized by IGF2BP3, further underscoring its potential as a highly specific therapeutic candidate.

These effects were far weaker in cells where IGF2BP3 had been genetically deleted, offering strong evidence that the molecule is working exactly where intended. Additional gene expression, RNA binding, thermal shift and drug-stability assays confirmed that I3IN-002 physically binds to IGF2BP3 and alters its function, one of the clearest demonstrations to date that this long-considered "undruggable" class of RNA-binding proteins can, in fact, be targeted with small molecules.

In preliminary mouse studies, the compound showed biological activity with modest but measurable anti-leukemia effects. Though the in-vivo impact was smaller than hoped, Rao emphasizes that this is expected for a first-generation molecule.

"What matters most is that we proved we can hit the protein and disrupt its biology," he said. "It's a step forward not just for leukemia research, but for the entire field of RNA-binding proteins in cancer."

Other UCLA authors are Georgia Scherer, Michelle Thaxton, Jacob Sorrentino, Constance Yuen, Milauni Mehta, Gunjan Sharma, Tasha Lin, Tiffany Tran, Amanda Cohen, Robert Damoiseaux and Neil Garg.

The work was supported in part by grants from the California Institute of Regenerative Medicine, the National Institutes of Health, the UCLA Health Jonsson Comprehensive Cancer Center, the Gary & Barbara Luboff Mitzvah Fund and the UCLA Innovation Fund Award, which helps advance promising discoveries toward commercialization.

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University of California - Los Angeles Health Sciences

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