Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases.
Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases.
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DOI：
10.1002/cbic.202200706
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发表时间：
2023-05-16
期刊：
影响因子：
3.2
通讯作者：
Shah, Neel H.
中科院分区：
文献类型：
--
作者：
Hong, Suk ho;Xi, Sarah Y.;Johns, Andrew C.;Tang, Lauren C.;Li, Allyson;Hum, Madeleine N.;Chartier, Cassandra A.;Jovanovic, Marko;Shah, Neel H.
Protein tyrosine phosphatases (PTPs) are an important class of enzymes that modulate essential cellular processes through protein dephosphorylation and are dysregulated in various disease states. There is demand for new compounds that target the active sites of these enzymes, for use as chemical tools to dissect their biological roles or as leads for the development of new therapeutics. In this study, we explore an array of electrophiles and fragment scaffolds to investigate the required chemical parameters for covalent inhibition of tyrosine phosphatases. Our analysis juxtaposes the intrinsic electrophilicity of these compounds with their potency against several classical PTPs, revealing chemotypes that inhibit tyrosine phosphatases while minimizing excessive, potentially non-specific reactivity. We also assess sequence divergence at key residues in PTPs to explain their differential susceptibility to covalent inhibition. We anticipate that our study will inspire new strategies to develop covalent probes and inhibitors for tyrosine phosphatases. Covalent chemical probes and inhibitors for tyrosine phosphatases have historically been challenging to develop. We report the characterization of diverse cysteine-reactive electrophiles and fragment-like scaffolds as covalent ligands for tyrosine phosphatases. Our investigation reveals chemical constraints for tyrosine phosphatase covalent inhibitor design and sheds light on the structural features of phosphatases that govern their susceptibility to covalent inhibition.
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影响因子：
7.3
作者：
Chen, Mark J.;Dixon, Jack E.;Manning, Gerard
通讯作者：
Manning, Gerard
DOI：
10.1073/pnas.0804336105
发表时间：
2008-07-22
影响因子：
11.1
作者：
Boivin, Benoit;Zhangt, Sheng;Tonks, Nicholas K.
通讯作者：
Tonks, Nicholas K.
DOI：
10.1002/chem.201705194
发表时间：
2018-06-04
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Casey GR;Stains CI
通讯作者：
Stains CI
影响因子：
64.5
作者：
Bar-Peled L;Kemper EK;Suciu RM;Vinogradova EV;Backus KM;Horning BD;Paul TA;Ichu TA;Svensson RU;Olucha J;Chang MW;Kok BP;Zhu Z;Ihle NT;Dix MM;Jiang P;Hayward MM;Saez E;Shaw RJ;Cravatt BF
通讯作者：
Cravatt BF
影响因子：
120.1
作者：
Boike, Lydia;Henning, Nathaniel J.;Nomura, Daniel K.
通讯作者：
Nomura, Daniel K.