癌症是一项全球性的健康挑战，目前仍然是一个大量研究的领域，旨在寻找新的抗癌治疗方法。其中，20S蛋白酶复合物是抗癌药物的一个靶标，与多种癌症类型相关。在本文中，我们旨在讨论20S蛋白酶亚基，并调查目前正在研究的针对催化活性蛋白酶亚基的蛋白酶抑制剂。在本综述中，我们总结了20S蛋白酶复合物的蛋白质降解机制，并将其与26S蛋白酶复合物进行比较。随后，总结了20S蛋白酶的定位以及其作为诊断和预后标记的用途。总结了经FDA批准进行临床试验的蛋白酶抑制剂（PIs），以及它们在固体肿瘤中目前有限的使用，还总结了β5亚基在不同细胞系中的表达情况。本综述讨论了20S蛋白酶复合物活性亚单位的计算机模拟分析。为了开发新的蛋白酶抑制剂药物，总结了抑制20S蛋白酶的天然产物，以及关于编码它们的生物合成基因簇的新方法和挑战的当前信息。我们在此简要总结了一些蛋白酶抑制剂的耐药机制。此外，我们关注三个主要的蛋白酶抑制剂类别：1] 硼酸，2] β-内酰胺和3] 环氧酮抑制剂类，并且总结了它们的IC50值及其结构活性关系（SAR）。最后，我们总结了几个开发新的蛋白酶抑制剂治疗肿瘤，特别是固体肿瘤的未来前景。版权所有©2023 Elsevier Inc.。保留所有权利。

Cancer is a global health challenge that remains to be a field of extensive research aiming to find new anticancer therapeutics. The 20S proteasome complex is one of the targets of anticancerdrugs, as it is correlated with several cancer types. Herein, we aim to discuss the 20S proteasome subunits and investigatethe currently studied proteasome inhibitors targeting the catalytically active proteasome subunits. In this review, we summarize the proteindegradation mechanism of the 20S proteasome complex and compareit with the 26S proteasome complex. Afterwards, the localization of the 20S proteasome is summarized as well as its use as a diagnosticandprognostic marker. The FDA-approved proteasome inhibitors (PIs) under clinical trials are summarized and their current limited use in solid tumors is also reviewed in addition to the expression of theβ5 subunit in differentcell lines. The review discusses in-silico analysis of the active subunit of the 20S proteasome complex. For development of new proteasome inhibitor drugs, the natural products inhibiting the 20S proteasome are summarized, as well as novel methodologies and challenges for the natural product discovery and current information about the biosynthetic gene clusters encoding them. We herein briefly summarize some resistancemechanismsto the proteasomeinhibitors. Additionally, we focus on the three main classes of proteasome inhibitors: 1] boronic acid, 2] beta-lactone and 3] epoxide inhibitor classes, as well as other PI classes, and their IC50 values and their structure-activity relationship (SAR). Lastly,we summarize several future prospects of developing new proteasome inhibitors towards the treatment of tumors, especially solid tumors.Copyright © 2023 Elsevier Inc. All rights reserved.