TY - JOUR
T1 - A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice
AU - Illendula, Anuradha
AU - Pulikkan, John A.
AU - Zong, Hongliang
AU - Grembecka, Jolanta
AU - Xue, Liting
AU - Sen, Siddhartha
AU - Zhou, Yunpeng
AU - Boulton, Adam
AU - Kuntimaddi, Aravinda
AU - Gao, Yan
AU - Rajewski, Roger A.
AU - Guzman, Monica L.
AU - Castilla, Lucio H.
AU - Bushweller, John H.
N1 - Publisher Copyright:
© 2015, American Association for the Advancement of Science. All rights reserved.
PY - 2015/2/13
Y1 - 2015/2/13
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aaa0314
DO - 10.1126/science.aaa0314
M3 - Article
C2 - 25678665
AN - SCOPUS:84922949970
SN - 0036-8075
VL - 347
SP - 779
EP - 784
JO - Science
JF - Science
IS - 6223
ER -
