Allardyce Duncan, Adu Mantey Priscilla, Szalecka Monika, Nkwo Robert, Loizidou Eriketi Z
Faculty of Science and Technology, Department of Natural Sciences, Middlesex University The Burroughs London NW4 4BT UK
RSC Med Chem. 2023 Feb 6;14(3):573-582. doi: 10.1039/d2md00404f. eCollection 2023 Mar 22.
Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of proteasomes disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors. In this work, we report the identification of a new class of proteasome inhibitors, polycyclic molecules bearing a naphthyl-azotricyclic-urea-phenyl scaffold, from screening of the ZINC library of natural products. The most potent of these compounds showed evidence of dose dependency through proteasome assays with IC values in the low micromolar range, and kinetic analysis revealed competitive binding at the β5c site with an estimated inhibition constant, , of 1.15 μM. Inhibition was also shown for the β5i site of the immunoproteasome at levels similar to those of the constitutive proteasome. Structure-activity relationship studies identified the naphthyl substituent to be crucial for activity and this was attributed to enhanced hydrophobic interactions within β5c. Further to this, halogen substitution within the naphthyl ring enhanced the activity and allowed for π-π interactions with Y169 in β5c and Y130 and F124 in β5i. The combined data highlight the importance of hydrophobic and halogen interactions in β5 binding and assist in the design of next generation inhibitors of proteasomes.
蛋白酶体通过维持蛋白质平衡在蛋白质降解和许多细胞通路的调节中发挥重要作用。蛋白酶体抑制剂会破坏这种平衡，影响恶性肿瘤中的关键蛋白质，因此已在多发性骨髓瘤和套细胞淋巴瘤的治疗中得到应用。然而，已经报道了这些蛋白酶体抑制剂的耐药机制，包括β5位点的突变，这就需要不断开发新的抑制剂。在这项工作中，我们报告了从天然产物的ZINC库筛选中鉴定出一类新的蛋白酶体抑制剂，即带有萘基 - 氮杂三环 - 脲 - 苯基支架的多环分子。这些化合物中最有效的通过蛋白酶体测定显示出剂量依赖性证据，IC值在低微摩尔范围内，动力学分析表明在β5c位点存在竞争性结合，估计抑制常数 为1.15 μM。对免疫蛋白酶体的β5i位点也显示出与组成型蛋白酶体相似水平的抑制作用。构效关系研究确定萘基取代基对活性至关重要，这归因于β5c内增强的疏水相互作用。此外，萘环内的卤素取代增强了活性，并允许与β5c中的Y169以及β5i中的Y130和F124形成π-π相互作用。综合数据突出了疏水和卤素相互作用在β5结合中的重要性，并有助于设计下一代蛋白酶体抑制剂。
