Defining degradability landscape of protein degraders

Defining degradability landscape of protein degraders | 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PDF Article Defining degradability landscape of protein degraders Olivier Elemento, Wei Du This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4254960/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Targeted protein degradation (TPD) is an emerging therapeutic modality. But how degradation efficacy is jointly determined by factors underlying this multi-step process is poorly understood. Here we present a succinct quantitative framework for modeling cellular mechanism of action of protein degraders, allowing for prediction of their cellular efficacy with practically obtainable parameters. Applying this model to published data on 41 different targets revealed a universal range of degradation rate around 1 min-1, which reflected the efficiency characteristic of TPD process. To provide a holistic characterization of degradation propensity of a target of interest, we define “degradability landscape”, and showed how it’s influenced by key factors. For kinase targets, we further quantified functional inhibition that enabled direct comparison between degrader and small molecule inhibitors. From above analysis, we derived several general guidelines for achieving potent degradation and proposed significant development opportunities of protein degraders from advantageous efficacy aspect. Biological sciences/Systems biology/Computer modelling Biological sciences/Computational biology and bioinformatics/Computational models Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SI.pdf Cite Share Download PDF Status: Under Review 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. 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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-4254960","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":292871415,"identity":"e44a92b2-675a-4834-a5d7-3d1f49eddbea","order_by":0,"name":"Olivier Elemento","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYDACdgbGBwkGEnJApgFUhLmBgYENjxZmBmaDDxUWxggtzIwEtbBJzjhTkdhAtBZ+ZuYD0rxtEulr25s3MPyouJfHD9LyoewwTi2SzWwJxkAtudvOHCtg7DlTXCzZzNjAOOMcbi0Gh3kMksFabuQYMDO2JSRuOMzYwMzbhk8L/4fDIIeZ3X8D0bIfpOUvXi08jI0zzkgkmN3ggdoC9AuQgdcvxgwfKiQMt51JKzjYcyYhcQbQloM959JxauFnb37+I8GgTt7s+OGND35UJCT2tzcffPCjzBqnFhRwAIMxCkbBKBgFo4A8AAA+mVZF56allwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8061-9617","institution":"Cornell University","correspondingAuthor":true,"prefix":"","firstName":"Olivier","middleName":"","lastName":"Elemento","suffix":""},{"id":292871416,"identity":"1c41004e-5afa-47c5-9aa0-e0b57f7e2e11","order_by":1,"name":"Wei Du","email":"","orcid":"","institution":"Yangtze River Pharmaceutical Group","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Du","suffix":""}],"badges":[],"createdAt":"2024-04-12 02:55:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4254960/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4254960/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60960286,"identity":"ddb7e3cd-4f7b-4f8a-bf2b-3334eac06c56","added_by":"auto","created_at":"2024-07-24 04:39:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":10851969,"visible":true,"origin":"","legend":"Article File","description":"","filename":"manuscriptmerged.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4254960/v1_covered_98f2e545-b425-4154-9fe0-d4b22e7b0509.pdf"},{"id":60959925,"identity":"16fef574-0c5d-4f48-88a3-cf151843216e","added_by":"auto","created_at":"2024-07-24 04:30:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":542919,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4254960/v1/4b69f5e284fd2301661b3ff1.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Defining degradability landscape of protein degraders","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-4254960/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4254960/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Targeted protein degradation (TPD) is an emerging therapeutic modality. 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