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.histone deacetylase 6 | proteasome inhibitor | multiple myeloma | bortezomib-resistance | WT161

Novel histone deacetylase inhibitors bearing a 4‐piperidin‐4‐yl‐triazole scaffold as antitumor agents

“…WY‐15 also displayed pan‐HDACs inhibitory activity with slight selectivity to HDAC6 and 8. Published studies demonstrated that HDAC6 and HDAC8 inhibitors can potently kill the MM cells (Hideshima et al, ) and neuroblastoma cells (Heimburg et al, ), respectively, so, the isoform selectivity result was consistent with the cell level results that WY‐15 exhibited potent growth inhibition activities toward NCI‐H929 (MM) and Sy5y (neuroblastoma) cells.…”

Selective pharmacological inhibitors of HDAC6 reveal biochemical activity but functional tolerance in cancer models

“…50 Nonetheless, promising results have been obtained combining selective HDAC6i at low concentrations with Temozolomide, an alkylating agent used for the treatment of glioblastoma multiforme, or with Cisplatin in non-small cell lung cancer cells. 55,[57][58][59] All together, these results call for caution when claiming synergy between HDAC6i and proteasome inhibitors. In most cases Ricolinostat was used, but with concentrations ranging from 1 to 4 μM, this approach is likely to result in off-target effects on other HDACs.…”

“…56 Synergistic effects combining Tubacin or Tubastatin A and Bortezomib/Carfilzomib when used against multiple myeloma, breast cancer and ovarian cancer, were only present at high molarities. 55,[57][58][59] All together, these results call for caution when claiming synergy between HDAC6i and proteasome inhibitors.…”

Epigenetic regulatory mutations and epigenetic therapy for multiple myeloma

“…Preclinical studies showed that HDACi in combination with proteasome inhibitors blocking protein degradation pathways were effective at eliminating MM cells (102–105). Therefore, efforts have been made to develop HDAC6 inhibitors with enhanced specificity (106). One such inhibitor, Ricolinostat (ACY-1215) demonstrated some antitumor activity in combination therapy (107).…”