Quantitative Measurement of Rate of Targeted Protein Degradation

降级(电信) 蛋白质降解 计算生物学 化学 生物 生物化学 计算机科学 电信
作者
Thomas L. Lynch,Violeta L. Marin,Ryan A. McClure,Colin Phipps,J.A. Ronau,Milad Rouhimoghadam,Ashley M. Adams,Soumya Kandi,Malerie L. Wolke,Andrea G. Shergalis,Gregory K. Potts,Omprakash Nacham,Paul L. Richardson,Stephan J. Kakavas,G. Chhor,Gary J. Jenkins,Kevin R. Woller,Scott E. Warder,Anil Vasudevan,Justin M. Reitsma
出处
期刊:ACS Chemical Biology [American Chemical Society]
卷期号:19 (7): 1604-1615 被引量:7
标识
DOI:10.1021/acschembio.4c00262
摘要

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects. However, apart from one in vitro study, studies supporting the catalytic mechanism of degraders are largely inferred based on potency. A more comprehensive understanding of the degrader catalytic mechanism of action can help aspects of compound development. To address this knowledge gap, we developed a workflow for the quantitative measurement of the catalytic rate of degraders in cells. Comparing a selective and promiscuous BTK degrader, we demonstrate that both compounds function as efficient catalysts of BTK degradation, with the promiscuous degrader exhibiting faster rates due to its ability to induce more favorable ternary complexes. By leveraging computational modeling, we show that the catalytic rate is highly dynamic as the target is depleted from cells. Further investigation of the promiscuous kinase degrader revealed that the catalytic rate is a better predictor of optimal degrader activity toward a specific target compared to degradation magnitude alone. In summary, we present a versatile method for mapping the catalytic activity of any degrader for TPD in cells.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
烟花应助啵萝味儿的奶盖采纳,获得10
刚刚
vincentbioinfo完成签到,获得积分10
刚刚
WJH发布了新的文献求助10
刚刚
量子星尘发布了新的文献求助10
2秒前
12we完成签到 ,获得积分10
3秒前
3秒前
4秒前
学不懂数学应助茶茶采纳,获得20
4秒前
隐形曼青应助旧辞采纳,获得10
4秒前
何佳完成签到,获得积分10
5秒前
烟花应助coco采纳,获得10
5秒前
小晶完成签到,获得积分10
5秒前
zimablue完成签到,获得积分10
6秒前
慕青应助范先生采纳,获得10
6秒前
zzz完成签到,获得积分10
7秒前
8秒前
海盗船长完成签到,获得积分10
8秒前
等待寄云完成签到 ,获得积分10
8秒前
酷波er应助王冉冉采纳,获得10
9秒前
lcjynwe完成签到,获得积分10
10秒前
新奇完成签到 ,获得积分10
10秒前
Misty_发布了新的文献求助10
10秒前
iNk应助不会取名字采纳,获得20
10秒前
Orange应助Hannes采纳,获得10
10秒前
12秒前
多多少少忖测的情完成签到,获得积分10
12秒前
小马甲应助lx采纳,获得10
12秒前
13秒前
阔达冰兰发布了新的文献求助10
13秒前
GAO完成签到,获得积分10
13秒前
yy发布了新的文献求助10
14秒前
14秒前
14秒前
奋斗冬萱完成签到,获得积分10
14秒前
康园完成签到,获得积分10
15秒前
活泼的面包完成签到,获得积分10
17秒前
123456完成签到,获得积分10
18秒前
重要谷冬完成签到,获得积分10
18秒前
深情丸子发布了新的文献求助10
18秒前
18秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
Research on Disturbance Rejection Control Algorithm for Aerial Operation Robots 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038524
求助须知:如何正确求助?哪些是违规求助? 3576221
关于积分的说明 11374737
捐赠科研通 3305912
什么是DOI,文献DOI怎么找? 1819354
邀请新用户注册赠送积分活动 892688
科研通“疑难数据库(出版商)”最低求助积分说明 815048