Journal of Molecular Biology, volume 434, issue 17, pages 167626
Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families
Publication type: Journal Article
Publication date: 2022-09-01
Journal:
Journal of Molecular Biology
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.6
ISSN: 00222836, 10898638
Molecular Biology
Structural Biology
Abstract
Allosteric mechanisms are pervasive in nature, but human-designed allosteric perturbagens are rare. The history of KRASG12C inhibitor development suggests that covalent chemistry may be a key to expanding the armamentarium of allosteric inhibitors. In that effort, irreversible targeting of a cysteine converted a non-deal allosteric binding pocket and low affinity ligands into a tractable drugging strategy. Here we examine the feasibility of expanding this approach to other allosteric pockets of RAS and kinase family members, given that both protein families are regulators of vital cellular processes that are often dysregulated in cancer and other human diseases. Moreover, these heavily studied families are the subject of numerous drug development campaigns that have resulted, sometimes serendipitously, in the discovery of allosteric inhibitors. We consequently conducted a comprehensive search for cysteines, a commonly targeted amino acid for covalent drugs, using AlphaFold-generated structures of those families. This new analysis presents potential opportunities for allosteric targeting of validated and understudied drug targets, with an emphasis on cancer therapy.
Top-30
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1 publication, 12.5%
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Citations by publishers
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Elsevier
4 publications, 50%
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Multidisciplinary Digital Publishing Institute (MDPI)
1 publication, 12.5%
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American Chemical Society (ACS)
1 publication, 12.5%
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1 publication, 12.5%
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Taylor & Francis
1 publication, 12.5%
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Li L. et al. Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families // Journal of Molecular Biology. 2022. Vol. 434. No. 17. p. 167626.
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Li L., Meyer C., Zhou Z., Elmezayen A., Westover K. D. Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families // Journal of Molecular Biology. 2022. Vol. 434. No. 17. p. 167626.
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TY - JOUR
DO - 10.1016/j.jmb.2022.167626
UR - https://doi.org/10.1016/j.jmb.2022.167626
TI - Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families
T2 - Journal of Molecular Biology
AU - Li, Lianbo
AU - Meyer, Cynthia
AU - Zhou, Zhiwei
AU - Elmezayen, Ammar
AU - Westover, Kenneth D.
PY - 2022
DA - 2022/09/01 00:00:00
PB - Elsevier
SP - 167626
IS - 17
VL - 434
SN - 0022-2836
SN - 1089-8638
ER -
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@article{2022_Li,
author = {Lianbo Li and Cynthia Meyer and Zhiwei Zhou and Ammar Elmezayen and Kenneth D. Westover},
title = {Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families},
journal = {Journal of Molecular Biology},
year = {2022},
volume = {434},
publisher = {Elsevier},
month = {sep},
url = {https://doi.org/10.1016/j.jmb.2022.167626},
number = {17},
pages = {167626},
doi = {10.1016/j.jmb.2022.167626}
}
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Li, Lianbo, et al. “Therapeutic Targeting the Allosteric Cysteinome of RAS and Kinase Families.” Journal of Molecular Biology, vol. 434, no. 17, Sep. 2022, p. 167626. https://doi.org/10.1016/j.jmb.2022.167626.