title: Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.
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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Teru
authors: T
authors: Hideshima
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Jun
authors: 0000-0002-1461-3356
authors: J
authors: Qi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Ronald M
authors: RM
authors: Paranal
authors: School of Pharmacology, University of Wisconsin-Madison, Madison, WI 53705.|Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors: Weiping
authors: W
authors: Tang
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Edward
authors: E
authors: Greenberg
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Nathan
authors: N
authors: West
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Meaghan E
authors: ME
authors: Colling
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.
authors: Guillermina
authors: G
authors: Estiu
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142.|Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02142.
authors: Ralph
authors: R
authors: Mazitschek
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Jennifer A
authors: JA
authors: Perry
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Hiroto
authors: H
authors: Ohguchi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Francesca
authors: F
authors: Cottini
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Naoya
authors: N
authors: Mimura
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Güllü
authors: G
authors: Görgün
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Yu-Tzu
authors: YT
authors: Tai
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Paul G
authors: PG
authors: Richardson
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.
authors: Ruben D
authors: RD
authors: Carrasco
authors: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556.|Laboratory of Computational Chemistry and Drug Discovery, Laboratory of Chemical Genomics, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
authors: Olaf
authors: O
authors: Wiest
authors: Broad Institute of Harvard and MIT, Cambridge, MA 02142.
authors: Stuart L
authors: SL
authors: Schreiber
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; james_bradner@dfci.harvard.edu kenneth_anderson@dfci.harvard.edu.
authors: Kenneth C
authors: KC
authors: Anderson
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; james_bradner@dfci.harvard.edu kenneth_anderson@dfci.harvard.edu.
authors: James E
authors: JE
authors: Bradner
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013730:Terphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D061988:Proteasome Inhibitors; D013730:Terphenyl Compounds; D014404:Tubulin; C000626829:WT161; C474316:tubacin; D000069286:Bortezomib; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6
keywords: WT161; bortezomib-resistance; histone deacetylase 6; multiple myeloma; proteasome inhibitor