Faculty Collaboration Database

Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science 2015 Feb 13;347(6223):779-84

Date

02/14/2015

Pubmed ID

25678665

Pubmed Central ID

PMC4423805

DOI

10.1126/science.aaa0314

Scopus ID

2-s2.0-84922949970 (requires institutional sign-in at Scopus site)   98 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.

Author List

Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH

Author

John A. Pulikkan PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Benzimidazoles
Cell Line, Tumor
Core Binding Factor Alpha 2 Subunit
Female
Humans
Leukemia, Myeloid, Acute
Mice
Mice, Inbred C57BL
Oncogene Proteins, Fusion
Protein Interaction Maps
Small Molecule Libraries