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Nat Commun. 2019 Jun 19;10(1):2691. doi: 10.1038/s41467-019-10523-3.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.

Author information

1
Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA.
2
Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
3
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
4
Structural Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
5
Weill Cornell Medical College, Tri-Institutional MD-PhD Program, Rockefeller University and Sloan Kettering Institute, New York, NY, 10065, USA.
6
Department of Pharmacology, Weill Cornell Graduate School of Medical Sciences, New York, NY, 10065, USA.
7
Chemical Biology Program, Sloan Kettering Institute and Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
8
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY, 10065, USA.
9
Schrödinger GmbH, Q7, 23, 68161, Mannheim, Germany.
10
High-Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, NY, 10065, USA.
11
Hematologic Oncology Tissue Bank, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
12
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
13
Northern Ontario School of Medicine, Sudbury, ON, P3E 2C6, Canada.
14
New York Structural Biology Center, NMR Group, New York, NY, 10027, USA.
15
Schrödinger, Inc., 120 West 45th Street, New York, NY, 10036, USA.
16
Molecular Pharmacology Program, Experimental Therapeutics Center and Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. kharasm@mskcc.org.

Abstract

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

PMID:
31217428
PMCID:
PMC6584500
DOI:
10.1038/s41467-019-10523-3
[Indexed for MEDLINE]
Free PMC Article

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