Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.
Rational design of proteasome inhibitors based on the structure of the endogenous inhibitor PI31/Fub1.
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基于内源抑制剂PI31/Fub1结构合理设计蛋白酶体抑制剂。
DOI：
10.1073/pnas.2308417120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Hanna,John
中科院分区：
文献类型：
--
作者：
Velez,Benjamin;Razi,Aida;Hubbard,RobertD;Walsh,Richard;Rawson,Shaun;Tian,Geng;Finley,Daniel;Hanna,John
蛋白酶体抑制剂是广泛应用的抗癌药物。这三种临床批准的药物都是修饰的小肽，在生理浓度下优先靶向蛋白酶体的三个活性位点之一(β5)。除了这些药物，还有一种内源性蛋白酶体抑制剂PI31/Fub1，它进入蛋白酶体内部，同时又特异性地抑制所有三个活性部位。在这里，我们使用PI31的S进化优化的抑制机制来开发一套有效和特异的β2抑制剂。该先导化合物作为一种独立的药物强烈抑制多发性骨髓瘤细胞的生长，表明该化合物具有细胞通透性，并使β-2成为治疗多发性骨髓瘤的潜在靶点。先导化合物与现有的β5抑制剂Bortezomib也显示出很强的协同作用；这种联合疗法可能有助于解决现有的耐药性挑战和严重的副作用。这些结果为合理结构指导开发蛋白酶体抑制剂提供了一种有效的方法。
Proteasome inhibitors are widely used anticancer drugs. The three clinically approved agents are modified small peptides that preferentially target one of the proteasome’s three active sites (β5) at physiologic concentrations. In addition to these drugs, there is also an endogenous proteasome inhibitor, PI31/Fub1, that enters the proteasome’s interior to simultaneously yet specifically inhibit all three active sites. Here, we have used PI31’s evolutionarily optimized inhibitory mechanisms to develop a suite of potent and specific β2 inhibitors. The lead compound strongly inhibited growth of multiple myeloma cells as a standalone agent, indicating the compound’s cell permeability and establishing β2 as a potential therapeutic target in multiple myeloma. The lead compound also showed strong synergy with the existing β5 inhibitor bortezomib; such combination therapies might help with existing challenges of resistance and severe side effects. These results represent an effective method for rational structure-guided development of proteasome inhibitors.