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There is currently no cure for multiple myeloma (MM), a fatal cancer of the plasma cells. Currently, proteasome inhibitors are used in the first-line treatment for patients with this disease. The proteasome is responsible for degradation of cellular proteins, which are overproduced in MM cells. Malignant cells become dependent on the proteasomal pathway, to the extent its inhibition causes cell death. However, akin to other cancers and multifactorial diseases, patients will develop resistance to this treatment and death becomes inevitable. One major resistance mechanism is activation of the aggresome pathway, an alternative method of protein degradation, which is reliant on histone deacetylase-6 (HDAC6) to transport protein aggregates to aggresomes until removal through autophagy. Recently, the combination of the HDAC6 inhibitor ricolinostat with bortezomib restored the efficacy of the proteasome inhibitor. Selective inhibition of HDAC6 may be beneficial by interrupting the aggresome pathway while also mitigating toxic effects seen with pan-inhibition of HDAC isozymes. HDAC inhibitors comprise a zinc binding group (ZBG), a linker, and a capping group; the latter two can be tailored to increase HDAC6 selectivity owing to the wider active site cavity of HDAC6. Capitalizing on the synergism reported between ricolinostat and bortezomib, and introducing a paradigm shift away from conventional drug cocktails we propose a polypharmacologic approach to novel treatments for MM. Guided by co-crystal structures, hydroxamic acid ZBGs will be grafted onto previously developed proteasome inhibitors to create dual HDAC6/proteasome inhibitors. There are several potential advantages to polypharmacology over combination treatments, perhaps the most important being a synergistic therapeutic effect due to the simultaneous presence of both pharmacophores in the site of therapeutic need (MM cells). Therefore, we hypothesize our dual inhibitors will produce a comparable therapeutic effect to the combination treatment of the respective parent drugs in vitro, but a superior efficacy in vivo.

Steven Fletcher

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