ArticleProceedings of the National Academy of Sciences of the United States of America2016
Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 136 citations in OpenAlex.
- Selective histone deacetylase inhibition as a therapeutically relevant strategy in H3K27M-glioma.Neuro-oncology · 2026Article
- Regulation of organic anion transporting polypeptide 1B1 transport function by lysine deacetylase 6.Molecular pharmacology · 2026Article
- Deciphering epigenetic crosstalk in multiple myeloma pathogenesis and treatment.Clinical epigenetics · 2026Review
- Post-translational regulation of organic anion transporting polypeptide 1B3 transport function by lysine acetylation and lysine deacetylase 6 inhibition.Drug metabolism and disposition: the biological fate of chemicals · 2026Article
- Capsaicin-Inspired Hydroxamate Hybrids as Selective HDAC6 Inhibitors with Antiproliferative Activity in Hematological Malignancies.ACS omega · 2026Article
- Selective HDAC6 inhibitor WT161 modulates the VLA-4/FAK pathway by inhibiting PKA activity in acute lymphoblastic leukemia.Scientific reports · 2025Article
- Histone deacetylase 6: A new player in oxidative stress‑associated disorders and cancers (Review).International journal of molecular medicine · 2025Review
- A novel indirubin- 3-monoxime derivative I3MV- 8b exhibits remarkable cytotoxicity against multiple myeloma by targeting TRIM28.Biomarker research · 2025Article
- Regulation of HDAC6 Catalytic Activity in Cancer: The Role of Post-Translational Modifications and Protein-Protein Interactions.International journal of molecular sciences · 2025Review
- WT161, a selective HDAC6 inhibitor, decreases growth, enhances chemosensitivity, promotes apoptosis, and suppresses motility of melanoma cells.Cancer chemotherapy and pharmacology · 2025Article
- DNMT3A loss drives a HIF-1-dependent synthetic lethality to HDAC6 inhibition in non-small cell lung cancer.Acta pharmaceutica Sinica. B · 2024Article
- Acquired Bortezomib Resistance in Multiple Myeloma: From Mechanisms to Strategy.Current treatment options in oncology · 2024Review
- HDAC6 Inhibition Releases HR23B to Activate Proteasomes, Expand the Tumor Immunopeptidome and Amplify T-cell Antimyeloma Activity.Cancer research communications · 2024Article
- In-Cell Testing of Zinc-Dependent Histone Deacetylase Inhibitors in the Presence of Class-Selective Fluorogenic Substrates: Potential and Limitations of the Method.Biomedicines · 2024Article
- Histone deacetylase inhibitors VPA and WT161 ameliorate the pathological features and cognitive impairments of the APP/PS1 Alzheimer's disease mouse model by regulating the expression of APP secretases.Alzheimer's research & therapy · 2024Article
- Endothelial cell elongation and alignment in response to shear stress requires acetylation of microtubules.Frontiers in physiology · 2024Article
- The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications.Frontiers in immunology · 2024Review
- Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?ChemMedChem · 2023Review
- Three-dimensional quantitative structural-activity relationship and molecular dynamics study of multivariate substituted 4-oxyquinazoline HDAC6 inhibitors.Molecular diversity · 2023Article
- Past, Present, and a Glance into the Future of Multiple Myeloma Treatment.Pharmaceuticals (Basel, Switzerland) · 2023Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
21 authors at 3 institutions in 2 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.