Abstract
ADVERTISEMENT RETURN TO ISSUEPREVFirst ReactionsNEXTHarnessing Antibody-Mimetic Selectivity for Activation-State-Specific Targeted Degradation of Endogenous K-RasInducible anti-Ras biodegraders as biological tools to interrogate nucleotide-loaded states across a panel of K-Ras mutants are developed.Fleur M. FergusonFleur M. FergusonDepartment of Chemistry & Biochemistry, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093-0657, United StatesE-mail: [email protected]More by Fleur M. Fergusonhttp://orcid.org/0000-0003-4091-7617Cite this: ACS Cent. Sci. 2021, 7, 2, 222–224Publication Date (Web):January 25, 2021Publication History Published online25 January 2021Published inissue 24 February 2021https://doi.org/10.1021/acscentsci.1c00084Copyright © Published 2021 by American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceCC: Creative CommonsBY: Credit must be given to the creatorNC: Only noncommercial uses of the work are permittedND: No derivatives or adaptations of the work are permittedArticle Views1719Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (2 MB) Get e-AlertsSUBJECTS:Degradation,Peptides and proteins,Genetics,Cells,Selectivity Get e-Alerts
Highlights
The Ras family of GTPases and are important but poorly druggable therapeutic targets that are frequently mutated in cancer. In this issue of ACS Central Science, Lim et al present the development of a panel of biodegraders that trigger rapid degradation of endogenous K-Ras proteins with conformational specificity.[1]
Small-molecule Ras inhibitor development is challenging due to the picomolar affinity these enzymes have for guanine nucleotides, which are present at high concentrations in the cell (0.1−1 mM)[3] and compete with inhibitors for active site binding
Other Ras mutants that lack a reactive cysteine proximal to the active site remain undrugged despite intensive efforts in the medicinal chemistry community.[4]
Summary
The Ras family of GTPases and are important but poorly druggable therapeutic targets that are frequently mutated in cancer In this issue of ACS Central Science, Lim et al present the development of a panel of biodegraders that trigger rapid degradation of endogenous K-Ras proteins with conformational specificity.[1]. Limitations of TPD include the requirement for small-molecule binders of the target protein and E3 ligase of interest, and the unknown compatibility of the target:E3 ligase pair.[5] A number of chemical genetic strategies have been developed to enable targeted protein degradation of unliganded proteins including K-RasG12V. Looking forward, applications of this approach may find utility for studying other high-value unliganded targets, for illuminating the functions of poorly understood proteins that lack chemical tools, and for prioritizing E3-ligases for ligand development efforts
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