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可降解激酶基因组的揭示有利于降解剂的研发
作者:小柯机器人 发布时间:2020/12/4 14:14:25

美国丹娜-法伯癌症研究所Eric S. Fischer、Nathanael S. Gray和韩国科学技术院Taebo Sim研究组,合作揭示了可降解激酶基因组蓝图并为降解剂的开发提供了参考。该项研究成果在线发表在2020年12月3日出版的《细胞》上。

研究人员利用蛋白质组学注释了可降解激酶基因组。该扩展数据集提供了约200种激酶的化学信息,并证明了目前从最高效能结合剂开始的实践对发现活性化合物是无效的。研究人员研发了多目标降解剂,以回答有关泛素蛋白酶体系统的基本问题,并发现激酶降解是p97依赖的。

这项工作不仅可以促进激酶降解剂的研发,而且还提供一个评估整个基因家族中靶向降解的蓝图,以加速对超越激酶组靶向蛋白质降解(TPD)的了解。

研究人员介绍,TPD是指利用小分子诱导蛋白质发生泛素依赖性降解。TPD在药物开发领域具有很高的潜能,因为它可以解决以前无法实现的难题。然而,由于缺乏对诱导靶标降解所需关键分子相对重要性的了解,降解剂的发现和优化效率极低。

附:英文原文

Title: Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development

Author: Katherine A. Donovan, Fleur M. Ferguson, Jonathan W. Bushman, Nicholas A. Eleuteri, Debabrata Bhunia, SeongShick Ryu, Li Tan, Kun Shi, Hong Yue, Xiaoxi Liu, Dennis Dobrovolsky, Baishan Jiang, Jinhua Wang, Mingfeng Hao, Inchul You, Mingxing Teng, Yanke Liang, John Hatcher, Zhengnian Li, Theresa D. Manz, Brian Groendyke, Wanyi Hu, Yunju Nam, Sandip Sengupta, Hanna Cho, Injae Shin, Michael P. Agius, Irene M. Ghobrial, Michelle W. Ma, Jianwei Che, Sara J. Buhrlage, Taebo Sim, Nathanael S. Gray, Eric S. Fischer

Issue&Volume: 2020-12-03

Abstract: Targeted protein degradation (TPD) refers to the use of small molecules to induceubiquitin-dependent degradation of proteins. TPD is of interest in drug development,as it can address previously inaccessible targets. However, degrader discovery andoptimization remains an inefficient process due to a lack of understanding of therelative importance of the key molecular events required to induce target degradation.Here, we use chemo-proteomics to annotate the degradable kinome. Our expansive datasetprovides chemical leads for ~200 kinases and demonstrates that the current practiceof starting from the highest potency binder is an ineffective method for discoveringactive compounds. We develop multitargeted degraders to answer fundamental questionsabout the ubiquitin proteasome system, uncovering that kinase degradation is p97 dependent.This work will not only fuel kinase degrader discovery, but also provides a blueprintfor evaluating targeted degradation across entire gene families to accelerate understandingof TPD beyond the kinome.

DOI: 10.1016/j.cell.2020.10.038

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)31445-8

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/