Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

The MUSASHI family of RNA binding proteins(MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We found that the small moleculeRo 08-2750 (Ro) directly binds to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemiacells resulted in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrated in vivo inhibition of c-MYC and reduced disease burdenin a murine AML leukemia model. Thus, we have identified a small moleculethat targets MSI9s oncogenic activity. Our study provides a framework for targeting RNA binding proteinsin cancer.