UCLA Researchers Develop First Small Molecule Inhibitor for 'Undruggable' Cancer Protein IGF2BP3
核心洞察
UCLA researchers have identified I3IN-002 (搜索), the first small molecule capable of inhibiting IGF2BP3 (搜索), a cancer-driving protein previously considered impossible to target with drugs.
The compound disrupts IGF2BP3 (搜索)'s ability to bind and stabilize cancer-promoting RNAs, triggering cancer cell death and reducing leukemia-initiating cells in laboratory studies.
This breakthrough represents a potential new therapeutic approach for aggressive acute leukemias and other hard-to-treat cancers including brain tumors, sarcomas, and breast cancers.
Researchers at the UCLA Health Jonsson Comprehensive Cancer Center (搜索) have achieved a significant breakthrough in cancer drug development by identifying the first small molecule capable of inhibiting IGF2BP3 (搜索), a cancer-driving protein that has long been considered "undruggable." The discovery, published in the journal Haematologica, could pave the way for new treatments for aggressive leukemias and other hard-to-treat cancers.
Targeting the Previously Untargetable
The compound, designated I3IN-002 (搜索), represents the culmination of more than a decade of research led by Dr. Dinesh Rao, professor of pathology and laboratory medicine at the David Geffen School of Medicine (搜索) at UCLA. "This project has been more than a decade in the making," said Rao, who serves as the study's senior author. "We discovered IGF2BP3 (搜索) years ago as an important driver in acute leukemias, and for a long time there were no tools to target it. To finally show that we can inhibit this protein and disrupt its function in cancer cells is incredibly exciting."
IGF2BP3 (搜索) belongs to a family of RNA-binding proteins that are normally active only during the earliest stages of human development. After birth, their activity largely shuts down, but in various cancers—including leukemia, brain tumors, sarcomas, and breast cancers—IGF2BP3 reactivates and drives tumor growth. The protein has proven notoriously difficult to target because it lacks the typical "pockets" or enzymatic features that most drugs use to bind to their targets.
Novel Screening Approach Yields Breakthrough
Rather than attempting to find traditional binding sites, the UCLA team developed an innovative approach focused on disrupting IGF2BP3 (搜索)'s core function: binding to RNA molecules that encode cancer-promoting genes. "RNA-binding proteins are not traditional cancer targets," explained Rao, who is also a member of the UCLA Health Jonsson Comprehensive Cancer Center (搜索) and the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. "But by understanding IGF2BP3's function and its job is to bind RNA that encodes cancer-promoting genes, we realized we could design an assay to disrupt that specific interaction."
The research team employed a high-throughput screening system to test approximately 200,000 compounds from the UCLA Molecular Screening Shared Resource, led by Dr. Robert Damoiseaux. This extensive screening aimed to identify candidates capable of blocking IGF2BP3 (搜索) from binding to its RNA targets—the core mechanism that enables the protein to drive cancer growth.
Compound Development and Validation
After identifying initial hit compounds, Rao collaborated with UCLA chemistry professor Dr. Neil Garg, whose group analyzed the compounds' structures and recognized preserved patterns. I3IN-002 (搜索) emerged as the lead compound, demonstrating potent activity at low micromolar concentrations and producing effects that closely mirrored complete IGF2BP3 (搜索) gene deletion. Garg's laboratory subsequently developed methods to synthesize the compound in-house, enabling further testing and development.
The researchers subjected I3IN-002 (搜索) to rigorous validation studies to confirm its mechanism of action. In leukemia cells dependent on IGF2BP3 (搜索) for growth, exposure to the molecule dramatically slowed proliferation, while cells lacking the protein showed minimal response—strong evidence that the compound acts on its intended target.
Promising Preclinical Results
In IGF2BP3 (搜索)-positive cells treated with I3IN-002 (搜索), the researchers observed multiple therapeutic effects. The molecule triggered apoptosis (programmed cell death) and interfered with the protein's RNA-binding ability, a critical step in its tumor-promoting activity. Additionally, the compound reduced expression of several cancer-promoting genes normally stabilized by IGF2BP3, further supporting its potential as a highly specific therapeutic candidate.
Importantly, these effects were significantly weaker in cells where IGF2BP3 (搜索) had been genetically deleted, providing strong evidence that the molecule works precisely as intended. Additional assays, including gene expression, RNA binding, thermal shift, and drug-stability studies, confirmed that I3IN-002 (搜索) physically binds to IGF2BP3 and alters its function.
Early Animal Studies and Future Directions
Preliminary mouse studies demonstrated that the compound showed biological activity with modest but measurable anti-leukemia effects. While the in-vivo impact was smaller than hoped, Rao emphasizes 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."
The research team is now focused on developing next-generation analogs of I3IN-002 (搜索) that are more potent, stable, and suitable for testing in animals and eventually humans. Dr. Amit Jaiswal, an assistant project scientist in the Rao Laboratory and first author of the study, noted that "from assay development to drug screening, hit validation, and downstream characterization, his work signifies a key milestone in our laboratory's research."
Broader Implications for Cancer Treatment
This breakthrough represents one of the clearest demonstrations to date that RNA-binding proteins, long considered "undruggable," can be targeted with small molecules. The success with IGF2BP3 (搜索) could open new avenues for treating not only acute leukemias but also other cancers where this protein plays a driving role, including brain tumors, sarcomas, and breast cancers.
The research was supported by grants from the California Institute of Regenerative Medicine, the National Institutes of Health, the UCLA Health Jonsson Comprehensive Cancer Center (搜索), the Gary & Barbara Luboff Mitzvah Fund, and the UCLA Innovation Fund Award, which helps advance promising discoveries toward commercialization.