{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:24:39Z","timestamp":1760059479444,"version":"build-2065373602"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"King Khalid University","award":["RGP2\/153\/46"],"award-info":[{"award-number":["RGP2\/153\/46"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Tankyrase (TNKS1) regulates the WNT\/\u03b2-catenin pathway, while CDK8 is a transcriptional regulator overexpressed in renal cell carcinoma (RCC). This study aims to identify novel dual inhibitors of tankyrase and Cyclin-dependent kinase 8 (CDK8), utilizing bioinformatics and in vitro methods and to assess their efficiency in renal cancer cells. Methods: To identify leads, the ChemBridge library was screening using high-throughput virtual screening (HTVS), which was followed by protein\u2013ligand interaction analysis, Molecular Dynamics (MD) simulation, and Gibbs binding free energy estimation. A-498, Caki-1, and HK-2 cells were employed to validate in vitro efficacy. Results: TCS9725 was discovered by HTVS with binding affinities of \u22128.1 kcal\/mol and \u22128.2 kcal\/mol for TNKS1 and CDK8, respectively. TCS9725 had robust binding interactions with root mean square deviation values of 0.00 nm. The \u0394G binding estimate was \u221227.45 for TNKS1 and \u221227.88 for CDK8, respectively. ADME predictions favored specific small-molecule inhibition profiles. TCS9725 reduced TNKS1 and CDK8 activities with IC50s of 243 nM and 403.6 nM, respectively. The compound efficiently inhibited the growth of A-498 and Caki-1 cells with GI50 values of 385.9 nM and 243.6 nM, respectively, with high selectivity compared to the non-cancerous kidney cells. TCS9725 decreased STAT1 and \u03b2-catenin positivity in A-498 and Caki-1 cells. The compound induced apoptosis and reduced TGF\u03b2-stimulated trans-endothelial migration and p-smad2\/3 signaling in both RCC cells. Conclusions: This work provides valuable insights into the therapeutic potential of TCS9725, a dual inhibitor of TNKS1 and CDK8. Further developments of this molecule could lead to new and effective treatments for this devastating disease.<\/jats:p>","DOI":"10.3390\/cimb47060463","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T05:52:47Z","timestamp":1750139567000},"page":"463","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Selective Dual Inhibition of TNKS1 and CDK8 by TCS9725 Attenuates STAT1\/\u03b2-Catenin\/TGF\u03b21 Signaling in Renal Cancer"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-6428-6278","authenticated-orcid":false,"given":"Majed Saad","family":"Al Fayi","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 31982, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mishari","family":"Alshyarba","sequence":"additional","affiliation":[{"name":"Department of Surgery, College of Medicine, King Khalid University, Abha 31982, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"79","DOI":"10.14740\/wjon1279","article-title":"Epidemiology of Renal Cell Carcinoma","volume":"11","author":"Padala","year":"2020","journal-title":"World J. 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