CLAMPs allow single cell tracking of KRASG12C inhibition and endow druggability to KRAS mutants

CLAMPs allow single cell tracking of KRASG12C inhibition and endow druggability to KRAS mutants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article CLAMPs allow single cell tracking of KRAS G12C inhibition and endow druggability to KRAS mutants Marie Evangelista, Chris Davies, Angela Oh, Rana Mroue, Melinda Mulvihil, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-133893/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2022 Read the published version in Nature Biotechnology → Version 1 posted You are reading this latest preprint version Abstract The discovery of covalent inhibitors binding the switch II (SWII) pocket has enabled therapeutic intervention in KRASG12C driven tumors and represents a milestone in targeting KRAS-driven cancers. However, the transient nature and high energetic barrier required for binding this pocket has been an obstacle in successfully targeting other KRAS mutant oncoproteins. We report the discovery of KRAS Conformation Locking Antibodies for Molecular Probe discovery (CLAMP)s that specifically recognize the unique conformation of KRASG12C induced by covalent inhibitors. KRAS CLAMPs enable single cell resolution of covalent inhibitor-bound KRASG12C in cells and in vivo tumor models, providing a biomarker for direct target engagement of KRASG12C inhibition. KRAS CLAMPs bind multiple KRAS mutants and stabilize an open conformation of the SWII pocket increasing the affinity of weak non-covalent SWII pocket ligands. This work provides new insights into KRASG12C upon treatment with covalent inhibitors and offers a path towards targeting the SWII pocket in other RAS mutants. Cancer Biology KRASG12C SWII pocket CLAMPs Full Text Additional Declarations Yes there is potential Competing Interest. Authors are employees of Genentech Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2022 Read the published version in Nature Biotechnology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-133893","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":8477881,"identity":"c68b9405-2461-4598-a6e5-e531078dbd3b","order_by":0,"name":"Marie 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to \u003cem\u003eKRAS\u003c/em\u003e mutants\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-133893/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"KRASG12C, SWII pocket, CLAMPs","lastPublishedDoi":"10.21203/rs.3.rs-133893/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-133893/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"The discovery of covalent inhibitors binding the switch II (SWII) pocket has enabled therapeutic intervention in KRASG12C driven tumors and represents a milestone in targeting KRAS-driven cancers. However, the transient nature and high energetic barrier required for binding this pocket has been an obstacle in successfully targeting other KRAS mutant oncoproteins. We report the discovery of KRAS Conformation Locking Antibodies for Molecular Probe discovery (CLAMP)s that specifically recognize the unique conformation of KRASG12C induced by covalent inhibitors. KRAS CLAMPs enable single cell resolution of covalent inhibitor-bound KRASG12C in cells and in vivo tumor models, providing a biomarker for direct target engagement of KRASG12C inhibition. KRAS CLAMPs bind multiple KRAS mutants and stabilize an open conformation of the SWII pocket increasing the affinity of weak non-covalent SWII pocket ligands. This work provides new insights into KRASG12C upon treatment with covalent inhibitors and offers a path towards targeting the SWII pocket in other RAS mutants.","manuscriptTitle":"CLAMPs allow single cell tracking of KRASG12C inhibition and endow druggability to KRAS mutants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-05-13 18:01:04","doi":"10.21203/rs.3.rs-133893/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-biotechnology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nbt","sideBox":"Learn more about [Nature Biotechnology](http://www.nature.com/nbt/)","snPcode":"","submissionUrl":"","title":"Nature Biotechnology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4caf0e2c-52da-4577-8132-c74242df93e1","owner":[],"postedDate":"May 13th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":4307215,"name":"Cancer Biology"}],"tags":[],"updatedAt":"2022-09-15T20:17:09+00:00","versionOfRecord":{"articleIdentity":"rs-133893","link":"https://doi.org/10.1038/s41587-021-01126-9","journal":{"identity":"nature-biotechnology","isVorOnly":false,"title":"Nature Biotechnology"},"publishedOn":"2022-01-06 05:00:00","publishedOnDateReadable":"January 6th, 2022"},"versionCreatedAt":"2021-05-13 18:01:04","video":"","vorDoi":"10.1038/s41587-021-01126-9","vorDoiUrl":"https://doi.org/10.1038/s41587-021-01126-9","workflowStages":[]},"version":"v1","identity":"rs-133893","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-133893","identity":"rs-133893","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}