Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.
Department of Pharmacy, Drug Discovery Laboratory, University of Naples Federico II, Via Domenico Montesano 49, 80131, Naples, Italy.
ChemMedChem. 2019 Apr 17;14(8):842-852. doi: 10.1002/cmdc.201900028. Epub 2019 Mar 26.
The development of immunoproteasome-selective inhibitors is a promising strategy for treating hematologic malignancies, autoimmune and inflammatory diseases. In this context, we report the design, synthesis, and biological evaluation of a new series of amide derivatives as immunoproteasome inhibitors. Notably, the designed compounds act as noncovalent inhibitors, which might be a promising therapeutic option because of the lack of drawbacks and side effects associated with irreversible inhibition. Among the synthesized compounds, we identified a panel of active inhibitors with K values in the low micromolar or sub-micromolar ranges toward the β5i and/or β1i subunits of immunoproteasomes. One of the active compounds was shown to be the most potent and selective inhibitor with a K value of 21 nm against the single β1i subunit. Docking studies allowed us to determine the mode of binding of the molecules in the catalytic site of immunoproteasome subunits.
免疫蛋白酶体选择性抑制剂的开发是治疗血液系统恶性肿瘤、自身免疫性和炎症性疾病的一种有前途的策略。在这方面，我们报告了一系列作为免疫蛋白酶体抑制剂的酰胺衍生物的设计、合成和生物学评价。值得注意的是，设计的化合物作为非共价抑制剂，由于缺乏与不可逆抑制相关的缺点和副作用，可能是一种有前途的治疗选择。在所合成的化合物中，我们鉴定了一组具有低微摩尔或亚微摩尔范围内的 K 值的活性抑制剂，针对免疫蛋白酶体的β5i 和/或β1i 亚基。其中一种活性化合物被证明是最有效和选择性的抑制剂，对单一的β1i 亚基的 K 值为 21nm。对接研究使我们能够确定分子在免疫蛋白酶体亚基催化位点的结合模式。
