Discovery of XZ338, a highly potent BCL-XL degrader

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-04-15 DOI:10.1016/j.ejmech.2025.117624

Xuan Zhang , Dinesh Thummuri , Wanyi Hu , Xingui Liu , Peiyi Zhang , Shuo Zhou , Daohong Zhou , Guangrong Zheng

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引用次数: 0

Abstract

BCL-X_L is a crucial anti-apoptotic protein involved in tumorigenesis and resistance to cancer chemotherapy. Transitioning from conventional inhibitors to PROTAC degraders has shown promising potential, particularly in minimizing the on-target thrombocytopenia linked to BCL-X_L inhibition. However, reported BCL-X_L degraders were mostly derived from BCL-X_L/BCL-2 dual inhibitor ABT-263, which also inhibits or degrades BCL-2 and can potentially cause neutropenia when combined with conventional chemotherapy as seen with ABT-263 in the clinic. The goal of the present study is to develop a highly specific BCL-X_L degrader without BCL-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-X_L degrader derived from BCL-X_L specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets.

Abstract Image

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发现XZ338，一种高效的BCL-XL降解剂

BCL-XL是一种重要的抗凋亡蛋白，参与肿瘤发生和对癌症化疗的耐药性。从传统抑制剂到PROTAC降解剂的过渡显示出很好的潜力，特别是在最小化与BCL-XL抑制相关的靶血小板减少方面。然而，报道的BCL-XL降降剂大多来自BCL-XL/BCL-2双抑制剂ABT-263， ABT-263也抑制或降解BCL-2，并且在与常规化疗联合使用时可能导致中性粒细胞减少，如ABT-263在临床上所见。本研究的目标是开发一种高度特异性的无BCL-2抑制/降解的BCL-XL降解剂。在本研究中，从BCL-XL特异性抑制剂a -1331852衍生出高效、选择性的BCL-XL降解剂XZ338。XZ338对MOLT-4 T-ALL细胞的效力是ABT-263的70倍，对MOLT-4细胞对人血小板的选择性超过89倍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.