Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBF?-SMMHC delays leukemia in mice.

ABSTRACT: Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBF?-SMMHC (core binding factor ? and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBF? for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBF?-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBF?-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers.

SUBMITTER: Illendula A 

PROVIDER: S-EPMC4423805 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature