New Molecule Shows Promise Against ‘Undruggable’ Cancer target

Researchers at the UCLA Health Jonsson Extensive Cancer Center have identified a small molecule that can inhibit a cancer-driving protein long considered impossible to target with drugs – a discovery that could open the door to a new class of treatments for leukemia and other hard-to-treat cancers.

The compound, called I3IN-002, disrupts the ability of a protein known as IGF2BP3 to bind and stabilize cancer-promoting RNAs. This mechanism fuels aggressive forms of acute leukemia.The study, published in the journal Haematologica, found the molecule not only slowed leukemic cell growth but also triggered cancer cell death and reduced the population of leukemia-initiating cells that sustain the disease.

“This project has been more than a decade in the making,” said 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 discovered IGF2BP3 years ago as an crucial 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 belongs to a family of RNA-binding proteins normally active only at the earliest stages of human growth. After birth, their activity largely shuts down, but in some cancers – including leukemia, brain tumors, sarcomas, and breast cancers – IGF2BP3 switches back on. For decades, researchers couldn’t develop a drug to disable it because IGF2BP3 lacks the typical “pockets” or enzymatic features that most drugs latch onto. This made it notoriously arduous to target.

“RNA-binding proteins are not traditional cancer targets,” said Rao, who is also a member of the UCLA Health Jonsson Comprehensive Cancer Center and the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. “But by understanding IGF2BP3’s function – its job is to bind RNA that encodes cancer-promoting genes – we realized we could design an assay to disrupt that specific interaction.”

To find a potential inhibitor,