UCLA Researchers discover ‘Undruggable’ Cancer Target, Paving Way for New Leukemia Treatments
A groundbreaking discovery by UCLA Health researchers has identified a small molecule capable of inhibiting a cancer-driving protein previously considered impossible to target with drugs, offering hope for new treatments for leukemia and other aggressive cancers.
Researchers at the UCLA Health Jonsson Comprehensive Cancer Center have achieved a notable breakthrough in cancer research, identifying a compound, dubbed I3IN-002, that disrupts the function of the protein IGF2BP3. This protein plays a crucial role in stabilizing RNAs that promote cancer growth, particularly in aggressive forms of acute leukemia. The findings, recently published in the journal Haematologica, demonstrate that I3IN-002 not only slowed the growth of leukemic cells but also induced cancer cell death and reduced the population of leukemia-initiating cells responsible for disease persistence.
“This project has been more than a decade in the making,” stated Dr. dinesh Rao,professor of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA and senior author of the study. “We realized that RNA that encodes cancer-promoting genes – we realized we could design an assay to disrupt that specific interaction.”
To identify a potential inhibitor, the research team screened approximately 200,000 compounds using a high-throughput system at the UCLA Molecular Screening Shared Resource, led by Dr. Robert Damoiseaux. This screening process aimed to find candidates that could block IGF2BP3 from binding to its RNA targets,effectively halting its cancer-driving function.
Following the identification of initial compounds, researchers collaborated with UCLA chemistry professor Dr. Neil Garg, whose lab analyzed the compounds’ structure and identified a recurring pattern. This led to the emergence of I3IN-002 as a leading candidate, demonstrating potent activity at low concentrations and mirroring the effects of complete IGF2BP3 gene deletion. Dr. Garg’s lab subsequently developed a method for synthesizing I3IN-002 in-house, a critical step for further testing.
Rigorous testing confirmed that I3IN-002 specifically targeted IGF2BP3. Leukemia cells reliant on IGF2BP3 for growth exhibited significantly slowed proliferation when exposed to the molecule, while cells lacking the protein showed minimal response. The compound also triggered apoptosis, or programmed cell death, and disrupted the protein’s ability to bind RNA, hindering its tumor-promoting activity. Furthermore, I3IN-002 reduced the expression of several cancer-promoting genes normally stabilized by IGF2BP3. These effects where substantially weaker in cells where IGF2BP3 had been genetically deleted, providing strong evidence of the molecule’s targeted action. Additional assays confirmed that I3IN-002 physically binds to and alters the function of IGF2BP3, demonstrating that this previously “undruggable” class of RNA-binding proteins can be targeted with small molecules.
Preliminary studies in mice showed biological activity with measurable anti-leukemia effects, although the impact was more modest than anticipated. rao emphasized that this is typical 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.”
The team is now focused on developing next-generation analogs of I3IN-002 with improved potency, stability, and suitability for animal and eventual human testing. “From assay advancement to drug screening, hit validation, and downstream characterization, his work signifies a key milestone in our laboratory’s research,” said Dr. Amit Jaiswal, an assistant project scientist in the Rao Laboratory and first author of the study.
The research involved contributions from several UCLA authors, including 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 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.
