Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST

Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST | 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 Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST Tom Schulz*, Maria Beerbaum*, Andrea Scrima*, Hannah Jantzen, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8307571/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 Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design novel inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 newly determined co-crystal structures, including the first structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure offers new insights for targeting solvent-front mutations across oncogenic kinases. *T. Schulz, M. Beerbaum, A. Scrima contributed equally. Biological sciences/Cancer/Sarcoma Biological sciences/Drug discovery/Medicinal chemistry/Structure-based drug design Full Text Additional Declarations Yes there is potential Competing Interest. S.B. reports grants and personal fees from Blueprint Medicines, Incyte, and Novartis, PharmaMar, Eli Lilly & Co, Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Cogent, Daiichi Sankyo, Deciphera, GSK, Exelixis, Novartis, Roche, PharmaMar. D.R. reports lecture and consulting fees from Pfizer, Sanofi, BI, and FLindr; is a shareholder of Centessa Pharmaceuticals plc., outside the submitted work. T.S., A.T., T.M., S.S., S.B, D.R. are co-inventors of a novel treatment against GIST (patent held by the respective institutions). Supplementary Files 9TFAD1292152468valreportfullannotateP1.pdf PDB validation report for structure 9TFA 9TF9D1292152296valreportfullannotateP1.pdf PDB validation report for structure 9TF9 9TFBD1292152484valreportfullannotateP1.pdf PDB validation report for structure 9TFB 9TFCD1292152486valreportfullannotateP1.pdf PDB validation report for structure 9TFC 9TFFD1292152574valreportfullannotateP1.pdf PDB validation report for structure 9TFF 9TFHD1292152579valreportfullannotateP1.pdf PDB validation report for structure 9TFH 9TFID1292152580valreportfullannotateP1.pdf PDB validation report for structure 9TFI 9TFKD1292152590valreportfullannotateP1.pdf PDB validation report for structure 9TFK 9TFLD1292152594valreportfullannotateP1.pdf PDB validation report for structure 9TFL 9TFMD1292152597valreportfullannotateP1.pdf PDB validation report for structure 9TFM 9TFGD1292152577valreportfullannotateP1.pdf PDB validation report for structure 9TFG 9TFED1292152572valreportfullannotateP1.pdf PDB validation report for structure 9TFE 9TFJD1292152587valreportfullannotateP1.pdf PDB validation report for structure 9TFJ 04122025SISchulzBeerbaumScrimaetalStructurebasedScaffoldHoppingFinalforsubmission.pdf Supplementary Information 9TFDD1292152528valreportfullannotateP1.pdf PDB validation report for structure 9TFD ArticleSchulzBeerbaumScrimaetalnrreportingsummary.pdf Reporting Summary 12122025SISchulzBeerbaumScrimaetalStructurebasedScaffoldHoppingFinalforsubmission.pdf Supplementary Information 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. 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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-8307571","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":569562371,"identity":"12b6fa55-7ce9-4af4-9f04-f08a6b83e1c1","order_by":0,"name":"Tom 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03:19:18","extension":"pdf","order_by":17,"title":"","display":"","copyAsset":false,"role":"supplement","size":12739174,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"12122025SISchulzBeerbaumScrimaetalStructurebasedScaffoldHoppingFinalforsubmission.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8307571/v1/9cd39851495c9aa0e5d93090.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nS.B. reports grants and personal fees from Blueprint Medicines, Incyte, and Novartis, PharmaMar, Eli Lilly \u0026 Co, Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Cogent, Daiichi Sankyo, Deciphera, GSK, Exelixis, Novartis, Roche, PharmaMar. D.R. reports lecture and consulting fees from Pfizer, Sanofi, BI, and FLindr; is a shareholder of Centessa Pharmaceuticals plc., outside the submitted work. T.S., A.T., T.M., S.S., S.B, D.R. are co-inventors of a novel treatment against GIST (patent held by the respective institutions).","formattedTitle":"Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST","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-8307571/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8307571/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design novel inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 newly determined co-crystal structures, including the first structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure offers new insights for targeting solvent-front mutations across oncogenic kinases.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e*T. Schulz, M. Beerbaum, A. Scrima contributed equally.\u003c/strong\u003e\u003c/p\u003e","manuscriptTitle":"Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-07 03:19:13","doi":"10.21203/rs.3.rs-8307571/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":"1cc1492b-db3e-466a-a193-3e897057f64e","owner":[],"postedDate":"January 7th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":60601959,"name":"Biological sciences/Cancer/Sarcoma"},{"id":60601960,"name":"Biological sciences/Drug discovery/Medicinal chemistry/Structure-based drug design"}],"tags":[],"updatedAt":"2026-05-08T21:15:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-07 03:19:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8307571","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8307571","identity":"rs-8307571","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}