泛素蛋白酶体途径是真核细胞中主要的蛋白质降解通路。许多与蛋白酶体活性位点共价结合的抑制剂已被开发用于治疗血液肿瘤，但患者可能出现抗药性。为了克服活性位点蛋白酶体抑制剂的局限性，我们和其他人专注于开发针对19S调节粒子（19S RP）亚基的配体。其中一个19S RP亚基，Rpn-13，是一种泛素受体，对于血液肿瘤快速降解蛋白质以避免凋亡十分重要。报道过的Rpn-13抑制剂与Rpn-13的Pru结构域共价结合，已被证明在抗血液肿瘤中有效。本研究描述了TCL-1的发现，它是与Pru结构域非共价结合的配体。通过将TCL-1的羧酸基团优化为酯类，增加了它在血液肿瘤细胞系中的细胞毒性。总之，我们的数据为将来的药物化学优化提供了一个新的基础结构，用于靶向治疗Rpn-13。版权所有©2023 Elsevier出版。

The ubiquitin-proteasome system serves as the major proteolytic degradation pathway in eukaryotic cells. Many inhibitors that covalently bind to the proteasome's active sites have been developed for hematological cancers, but resistance can arise in patients. To overcome limitations of active-site proteasome inhibitors, we and others have focused on developing ligands that target subunits on the 19S regulatory particle (19S RP). One such 19S RP subunit, Rpn-13, is a ubiquitin receptor required for hematological cancers to rapidly degrade proteins to avoid apoptosis. Reported Rpn-13 inhibitors covalently bind to the Rpn-13's Pru domain and have been effective anti-hematological cancer agents. Here, we describe the discovery of TCL-1, a non-covalent binder to the Pru domain. Optimization of TCL-1's carboxylate group to an ester increases its cytotoxicity in hematological cancer cell lines. Altogether, our data provides a new scaffold for future medicinal chemistry optimization to target Rpn-13 therapeutically.Copyright © 2023. Published by Elsevier Ltd.