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Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 15; Vol. 113 (46), pp. 13162-13167. Date of Electronic Publication: 2016 Oct 31. - Publication Year :
- 2016
-
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.<br />Competing Interests: 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.
- Subjects :
- Anilides pharmacology
Anilides therapeutic use
Animals
Antineoplastic Agents pharmacology
Bortezomib pharmacology
Cell Line, Tumor
Cell Survival drug effects
Drug Resistance, Neoplasm
Histone Deacetylase 6 antagonists & inhibitors
Histone Deacetylase 6 metabolism
Histone Deacetylase Inhibitors pharmacology
Humans
Hydroxamic Acids pharmacology
Male
Mice
Multiple Myeloma metabolism
Proteasome Inhibitors pharmacology
Terphenyl Compounds pharmacology
Tubulin metabolism
Tumor Cells, Cultured
Antineoplastic Agents therapeutic use
Bortezomib therapeutic use
Histone Deacetylase Inhibitors therapeutic use
Hydroxamic Acids therapeutic use
Multiple Myeloma drug therapy
Proteasome Inhibitors therapeutic use
Terphenyl Compounds therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27799547
- Full Text :
- https://doi.org/10.1073/pnas.1608067113