CBP/Catenin Antagonist Safely Eliminates Drug Resistant Leukemia Initiating Cells

CBP and p300 are highly homologous transcriptional coactivators with unique, non-redundant roles that bind a wide array of proteins, including catenins – β and γ. ICG-001 is a small molecule inhibitor that specifically inhibits the CBP/catenin interaction. Importantly, ICG-001 does not inhibit the p300/catenin interaction. We demonstrate that specifically inhibiting the interaction between CBP and catenin with ICG-001, results in the differentiation of quiescent drug resistant chronic myelogenous leukemia initiating cells (CML-LICs), thereby sensitizing them to BCR-ABL tyrosine kinase inhibitors, e.g. Imatinib. Using ICG-001 in a NOD/SCID/IL2Rγ(−/−) mouse model of engrafted human chronic myelogenous leukemia, we now demonstrate the complete elimination of engrafted leukemia after only one course of combined chemotherapy. Combination-treated animals live as long as their non-engrafted littermates. Results from these studies demonstrate that specifically antagonizing the CBP/catenin interaction with ICG-001 can eliminate drug resistant CML-LICs without deleterious effects to the normal endogenous hematopoietic stem cell population.