Publication Date:
2015-02-14
Description:
Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFbeta-SMMHC (core binding factor beta and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFbeta 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 CBFbeta-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 CBFbeta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423805/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423805/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Illendula, Anuradha -- Pulikkan, John A -- Zong, Hongliang -- Grembecka, Jolanta -- Xue, Liting -- Sen, Siddhartha -- Zhou, Yunpeng -- Boulton, Adam -- Kuntimaddi, Aravinda -- Gao, Yan -- Rajewski, Roger A -- Guzman, Monica L -- Castilla, Lucio H -- Bushweller, John H -- 1 DP2 OD007399-01/OD/NIH HHS/ -- DP2 OD007399/OD/NIH HHS/ -- R01 AI039536/AI/NIAID NIH HHS/ -- R01 CA096983/CA/NCI NIH HHS/ -- R01 CA140398/CA/NCI NIH HHS/ -- T32 GM080186/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 13;347(6223):779-84. doi: 10.1126/science.aaa0314.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. ; Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA. ; Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA. ; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. ; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA. ; Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu. ; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. jhb4v@virginia.edu Lucio.Castilla@umassmed.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678665" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antineoplastic Agents/chemistry/*therapeutic use
;
Benzimidazoles/chemistry/*therapeutic use
;
Cell Line, Tumor
;
Core Binding Factor Alpha 2 Subunit/antagonists & inhibitors/metabolism
;
Female
;
Humans
;
Leukemia, Myeloid, Acute/*drug therapy
;
Mice
;
Mice, Inbred C57BL
;
Oncogene Proteins, Fusion/*antagonists & inhibitors/metabolism
;
Protein Interaction Maps
;
Small Molecule Libraries/chemistry
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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