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

Teru Hideshima, Jun Qi, Ronald M. Paranal, Weiping Tang, Edward Greenberg, Nathan West, Meaghan E. Colling, Guillermina Estiu, Ralph Mazitschek, Jennifer A. Perry, Hiroto Ohguchi, Francesca Cottini, Naoya Mimura, Güllü Görgün, Yu Tzu Tai, Paul G. Richardson, Ruben D. Carrasco, Olaf Wiest, Stuart L. Schreiber, Kenneth C. AndersonJames E. Bradner

Research output: Contribution to journalArticle

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)13162-13167
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number46
DOIs
StatePublished - Nov 15 2016

Keywords

  • Bortezomib-resistance
  • Histone deacetylase 6
  • Multiple myeloma
  • Proteasome inhibitor
  • WT161

ASJC Scopus subject areas

  • General

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    Hideshima, T., Qi, J., Paranal, R. M., Tang, W., Greenberg, E., West, N., Colling, M. E., Estiu, G., Mazitschek, R., Perry, J. A., Ohguchi, H., Cottini, F., Mimura, N., Görgün, G., Tai, Y. T., Richardson, P. G., Carrasco, R. D., Wiest, O., Schreiber, S. L., ... Bradner, J. E. (2016). Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma. Proceedings of the National Academy of Sciences of the United States of America, 113(46), 13162-13167. https://doi.org/10.1073/pnas.1608067113