A novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure

A novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure | 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 A novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure Eric Campeau, Sabindra Pradhananga, Dinesh Srinivasan, Marc Vidal, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7539711/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 Despite the advent of transformative guideline-directed therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide, underscoring an urgent need for novel therapies. Clinical benefits of contemporary interventions (sodium-glucose co-transporter-2 inhibitors, SGLT2i) in HF suggest the importance of metabolic modulation to complement classical neurohormonal blockade in HF pharmacotherapy. Serum glucocorticoid regulated kinase 1 (SGK1) has emerged as a prime stress-induced regulator of multiple metabolic-inflammatory pathways central to HF in model systems, though translation to patients is limited by absence of a selective, efficacious pharmacologic inhibitor. Here, we provide the first demonstration to our knowledge of a novel, phase 2 ready small molecule SGK1 inhibitor (THRV-SGK1i), demonstrating (1) human genetic and tissue evidence linking SGK1 with HF; (2) kinase selectivity, potency, pharmacodynamics, and SGK1 target engagement by THRV-SGK1i; (3) the beneficial effect of THRV-SGK1i on myocardial structure, function, and histopathology in a pressure-overload HF model alone or in combination with SGLT2i. The convergence of human genetic and tissue data, precision discovery-guided drug development, model system studies, and a comprehensive nonclinical safety package provide compelling evidence in support of the planned clinical studies of SGK1 inhibition in clinical HF. Health sciences/Cardiology/Cardiovascular biology Biological sciences/Drug discovery/Target validation Health sciences/Medical research/Translational research Full Text Additional Declarations Yes there is potential Competing Interest. S.P., D.S., E.C., M.V., D.L., K.F.B., A.B., PT, D.O., A.S. have received salary and equity from Thryv Therapeutics Inc. R.S. is supported by grants from the National Institutes of Health and has equity ownership in and is a consultant for Thryv Therapeutics Inc. R.S. is a co-inventor on pending patents or disclosures on molecular biomarkers of fitness, lung disease, cardiovascular diseases and phenotypes, and metabolic health, use of RNAs (including spatial) as therapeutics and diagnostic biomarkers in disease, and methods in metabolomics. SD is a founder and holds equity in Thryv therapeutics and Switch Therapeutics. He is a consultant for Thryv Therapeutics and has received grant support from Bristol Myers Squibb and Cytokinetics. He owns IP for 'Use of SGK1 in cardiovascular disease'. Supplementary Files SupplementaryDataFileGSEAofcellsubtypesscRNASeq02Sept1.xlsx Dataset 1 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. 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-7539711","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":538828581,"identity":"5e1c1241-6c9f-4382-bb26-b1b557f9d8c4","order_by":0,"name":"Eric Campeau","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYFACxgaGDwwHSNTCOCMBpIWZBE3MPCRp4Zc+3PjZ9sedfIMb+cc+8zDYyek2ENAi2ZfYLJ2T8Mxyw41k5pkzGJKNzQ4Q0GJwhrGNOSfhsIHBmcPMoHBI3EZIiz1IiwVMSwIxWgx4gFoYQFqONxNpi8QZxmbJnrTDBpLHm40ZZxgQ4Rf+HvaHH37YHDbgO8z4mJmnwk6OoBY4UACrNCBWOQjIN5CiehSMglEwCkYUAAAgjD+vdujesAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-7121-9785","institution":"Thryv Therapeutics Inc.","correspondingAuthor":true,"prefix":"","firstName":"Eric","middleName":"","lastName":"Campeau","suffix":""},{"id":538828582,"identity":"4753b8e2-f43d-499f-ba4d-ef174d82b179","order_by":1,"name":"Sabindra Pradhananga","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Sabindra","middleName":"","lastName":"Pradhananga","suffix":""},{"id":538828583,"identity":"f6ea7784-0b63-4db2-9c54-78da6dd18b7e","order_by":2,"name":"Dinesh Srinivasan","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Dinesh","middleName":"","lastName":"Srinivasan","suffix":""},{"id":538828584,"identity":"2c382cbc-03a7-41d6-8b3f-108e7e04df81","order_by":3,"name":"Marc Vidal","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Marc","middleName":"","lastName":"Vidal","suffix":""},{"id":538828585,"identity":"f3ec21e9-14a0-4b86-939d-547d669497f5","order_by":4,"name":"Delphine Labit","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Delphine","middleName":"","lastName":"Labit","suffix":""},{"id":538828586,"identity":"48348313-19da-47de-80a4-c12d69631465","order_by":5,"name":"Kayluz Frias Boligan","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Kayluz","middleName":"Frias","lastName":"Boligan","suffix":""},{"id":538828587,"identity":"744840ea-aa26-49a1-ac8d-471a88343ea8","order_by":6,"name":"Alexandre Brkovic","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Alexandre","middleName":"","lastName":"Brkovic","suffix":""},{"id":538828588,"identity":"e0b7fff6-29ec-491b-b2c9-c325cbb32c57","order_by":7,"name":"Paul Truex","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Truex","suffix":""},{"id":538828589,"identity":"35b654b1-8547-4432-93df-f9a2f1b2bcea","order_by":8,"name":"Debra Odink","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Debra","middleName":"","lastName":"Odink","suffix":""},{"id":538828590,"identity":"3950478d-ee2a-4bc2-a64c-6b0de14f4562","order_by":9,"name":"Amy Sehnert","email":"","orcid":"","institution":"Thryv Therapeutics Inc.","correspondingAuthor":false,"prefix":"","firstName":"Amy","middleName":"","lastName":"Sehnert","suffix":""},{"id":538828591,"identity":"ec0dfe44-89be-45cc-a407-365744364fa0","order_by":10,"name":"Eric Gamazon","email":"","orcid":"https://orcid.org/0000-0003-4204-8734","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Gamazon","suffix":""},{"id":538828592,"identity":"c6fdd884-4655-40c9-abe2-58d7904d3540","order_by":11,"name":"Ravi Shah","email":"","orcid":"https://orcid.org/0000-0002-4471-7156","institution":"VUMC","correspondingAuthor":false,"prefix":"","firstName":"Ravi","middleName":"","lastName":"Shah","suffix":""},{"id":538828593,"identity":"ab0b5275-5d2c-404b-89a7-4a0b5c7dc54f","order_by":12,"name":"Saumya Das","email":"","orcid":"https://orcid.org/0000-0002-4521-4606","institution":"Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA","correspondingAuthor":false,"prefix":"","firstName":"Saumya","middleName":"","lastName":"Das","suffix":""}],"badges":[],"createdAt":"2025-09-05 01:25:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7539711/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7539711/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":95514876,"identity":"d9704b29-8bfe-460f-ac2e-d7488debfca7","added_by":"auto","created_at":"2025-11-10 08:10:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":2849309,"visible":true,"origin":"","legend":"","description":"","filename":"100625THRVSGK1iTACcombopaperFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7539711/v1/eafb0591d4ddbcdda7a64440.pdf"},{"id":95514875,"identity":"406b82c3-a55a-4dfb-955a-96eee117dedb","added_by":"auto","created_at":"2025-11-10 08:10:32","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12589,"visible":true,"origin":"","legend":"","description":"","filename":"NCOMMS2572390A.json","url":"https://assets-eu.researchsquare.com/files/rs-7539711/v1/ddd3f33937fa60c19805ee45.json"},{"id":95529894,"identity":"a4177de2-d8ef-4b86-bfa8-869ca014561a","added_by":"auto","created_at":"2025-11-10 10:17:38","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2549557,"visible":true,"origin":"","legend":"Article File","description":"","filename":"100625THRVSGK1iTACcombopaperFINAL.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7539711/v1_covered_8d1365ac-9050-42ce-be12-ed718d78fbe1.pdf"},{"id":95514874,"identity":"e40f4180-2894-4ef8-8f80-d951d983a4bc","added_by":"auto","created_at":"2025-11-10 08:10:32","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24815,"visible":true,"origin":"","legend":"Dataset 1","description":"","filename":"SupplementaryDataFileGSEAofcellsubtypesscRNASeq02Sept1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7539711/v1/da310bc87d4b9f5d741b0972.xlsx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nS.P., D.S., E.C., M.V., D.L., K.F.B., A.B., PT, D.O., A.S. have received salary and equity from Thryv Therapeutics Inc. R.S. is supported by grants from the National Institutes of Health and has equity ownership in and is a consultant for Thryv Therapeutics Inc. R.S. is a co-inventor on pending patents or disclosures on molecular biomarkers of fitness, lung disease, cardiovascular diseases and phenotypes, and metabolic health, use of RNAs (including spatial) as therapeutics and diagnostic biomarkers in disease, and methods in metabolomics. SD is a founder and holds equity in Thryv therapeutics and Switch Therapeutics. He is a consultant for Thryv Therapeutics and has received grant support from Bristol Myers Squibb and Cytokinetics. He owns IP for 'Use of SGK1 in cardiovascular disease'.","formattedTitle":"\u003cp\u003eA novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure\u003c/p\u003e","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-7539711/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7539711/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Despite the advent of transformative guideline-directed therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide, underscoring an urgent need for novel therapies. Clinical benefits of contemporary interventions (sodium-glucose co-transporter-2 inhibitors, SGLT2i) in HF suggest the importance of metabolic modulation to complement classical neurohormonal blockade in HF pharmacotherapy. Serum glucocorticoid regulated kinase 1 (SGK1) has emerged as a prime stress-induced regulator of multiple metabolic-inflammatory pathways central to HF in model systems, though translation to patients is limited by absence of a selective, efficacious pharmacologic inhibitor. Here, we provide the first demonstration to our knowledge of a novel, phase 2 ready small molecule SGK1 inhibitor (THRV-SGK1i), demonstrating (1) human genetic and tissue evidence linking SGK1 with HF; (2) kinase selectivity, potency, pharmacodynamics, and SGK1 target engagement by THRV-SGK1i; (3) the beneficial effect of THRV-SGK1i on myocardial structure, function, and histopathology in a pressure-overload HF model alone or in combination with SGLT2i. The convergence of human genetic and tissue data, precision discovery-guided drug development, model system studies, and a comprehensive nonclinical safety package provide compelling evidence in support of the planned clinical studies of SGK1 inhibition in clinical HF. \r\n ","manuscriptTitle":"A novel serum glucocorticoid regulated kinase 1 inhibitor improves cardiac structure and function in heart failure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 08:10:28","doi":"10.21203/rs.3.rs-7539711/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":"890cbf02-23fb-43cc-b17a-cf47244f1be0","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":57707804,"name":"Health sciences/Cardiology/Cardiovascular biology"},{"id":57707805,"name":"Biological sciences/Drug discovery/Target validation"},{"id":57707806,"name":"Health sciences/Medical research/Translational research"}],"tags":[],"updatedAt":"2025-11-19T10:46:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-10 08:10:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7539711","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7539711","identity":"rs-7539711","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}