A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice

Anuradha Illendula, John A. Pulikkan, Hongliang Zong, Jolanta Grembecka, Liting Xue, Siddhartha Sen, Yunpeng Zhou, Adam Boulton, Aravinda Kuntimaddi, Yan Gao, Roger A. Rajewski, Monica L. Guzman, Lucio H. Castilla, John H. Bushweller

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFβ-SMMHC (core binding factor β and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFβ 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 CBFβ-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 CBFβ-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.

Original languageEnglish (US)
Pages (from-to)779-784
Number of pages6
JournalScience
Volume347
Issue number6223
DOIs
StatePublished - Feb 13 2015
Externally publishedYes

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© 2015, American Association for the Advancement of Science. All rights reserved.

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