Rational design of potent small molecule SMARCA2/A4(BRM/BRG1) degraders acting via the recruitment of FBXO22

Rational design of potent small molecule SMARCA2/A4(BRM/BRG1) degraders acting via the recruitment of FBXO22 | 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 Rational design of potent small molecule SMARCA2/A4(BRM/BRG1) degraders acting via the recruitment of FBXO22 Robert Yauch, Elisia Villemure, Tom Januario, Mingshuo Zeng, Hanna Budayeva, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6033426/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 03 Nov, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Target-anchored monovalent degraders are more drug-like than their bivalent counterparts, Proteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than the E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their discovery has typically been serendipitous, and the rules governing their identification remain unclear. This study focused on the intentional discovery of SMARCA2/A4 monovalent degraders using a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599 emerged as a lead candidate, showing exceptional degradation potency and specificity for SMARCA2/A4. Mechanistic studies revealed that G-6599 operates through the ubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 was shown to promote ternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to a cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it does not require biotransformation. The selective degradation ability of G-6599, along with its unique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders. Biological sciences/Chemical biology/Small molecules Biological sciences/Chemical biology/Mechanism of action Full Text Additional Declarations Yes there is potential Competing Interest. Authors are employees of Genentech and/or hold stock in Roche. Supplementary Files SupplementaryTable1.xlsx Supplementary Table Dataset 1 SupplementaryTable2.xlsx Supplementary Table Dataset 2 SupplementaryTable3.xlsx Supplementary Table Dataset 3 SupplementaryTable4.xlsx Supplementary Table Dataset 4 SupplementaryTable5.xlsx Supplementary Table Dataset 5 SupplementaryTable6.xlsx Supplementary Table Dataset 6 SupplementaryTable7.xlsx Supplementary Table Dataset 7 SupportingInformationRationaldesignofpotentsmallmoleculeSMARCA2A4BRMBRG1degradersactingviarecruitmentofFBXO22.pdf Supportive Information Cite Share Download PDF Status: Published Journal Publication published 03 Nov, 2025 Read the published version in Nature Communications → 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. 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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-6033426","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":420943131,"identity":"2311264e-c590-4499-8954-772f2673f0fc","order_by":0,"name":"Robert 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FBXO22","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"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-6033426/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6033426/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Target-anchored monovalent degraders are more drug-like than their bivalent counterparts,\r\nProteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than\r\nthe E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their\r\ndiscovery has typically been serendipitous, and the rules governing their identification remain\r\nunclear. This study focused on the intentional discovery of SMARCA2/A4 monovalent degraders\r\nusing a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599\r\nemerged as a lead candidate, showing exceptional degradation potency and specificity for\r\nSMARCA2/A4. Mechanistic studies revealed that G-6599 operates through the\r\nubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 was shown to promote\r\nternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to\r\na cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it\r\ndoes not require biotransformation. The selective degradation ability of G-6599, along with its\r\nunique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders.","manuscriptTitle":"Rational design of potent small molecule SMARCA2/A4(BRM/BRG1) degraders acting via the recruitment of FBXO22","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-10 04:09:48","doi":"10.21203/rs.3.rs-6033426/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3e808724-5b7c-41fb-9c8f-cfb34ba0e1a1","owner":[],"postedDate":"March 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":44871925,"name":"Biological sciences/Chemical biology/Small molecules"},{"id":44871926,"name":"Biological sciences/Chemical biology/Mechanism of action"}],"tags":[],"updatedAt":"2025-11-04T08:07:38+00:00","versionOfRecord":{"articleIdentity":"rs-6033426","link":"https://doi.org/10.1038/s41467-025-64669-4","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-11-03 05:00:00","publishedOnDateReadable":"November 3rd, 2025"},"versionCreatedAt":"2025-03-10 04:09:48","video":"","vorDoi":"10.1038/s41467-025-64669-4","vorDoiUrl":"https://doi.org/10.1038/s41467-025-64669-4","workflowStages":[]},"version":"v1","identity":"rs-6033426","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6033426","identity":"rs-6033426","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}