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Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13162-13167. Epub 2016 Oct 31.

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
2
School of Pharmacology, University of Wisconsin-Madison, Madison, WI 53705.
3
Broad Institute of Harvard and MIT, Cambridge, MA 02142.
4
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
5
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02142.
6
Laboratory of Computational Chemistry and Drug Discovery, Laboratory of Chemical Genomics, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; james_bradner@dfci.harvard.edu kenneth_anderson@dfci.harvard.edu.

Abstract

Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.

KEYWORDS:

WT161; bortezomib-resistance; histone deacetylase 6; multiple myeloma; proteasome inhibitor

PMID:
27799547
PMCID:
PMC5135369
DOI:
10.1073/pnas.1608067113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

T.H. is a consultant for Acetylon Pharmaceuticals. R.M. has financial interests in SHAPE Pharmaceuticals and Acetylon Pharmaceuticals and is the inventor on intellectual property licensed to these two entities. K.C.A. is an advisor for Celgene, Millennium Pharmaceuticals, and Gilead Sciences and is a Scientific Founder of OncoPep, Acetylon Pharmaceuticals, and C4 Therapeutics. J.E.B. is a Scientific Founder of SHAPE Pharmaceuticals, Acetylon Pharmaceuticals, Tensha Therapeutics, and C4 Therapeutics and is the inventor on intellectual property licensed to these entities. As of January 1, 2016, J.E.B. is an employee of the Novartis Institutes of Biomedical Research.

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