{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T15:28:09Z","timestamp":1793978889747,"version":"4.8.0"},"reference-count":41,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,12,1]],"date-time":"2026-12-01T00:00:00Z","timestamp":1796083200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81773640"],"award-info":[{"award-number":["81773640"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Medicinal Chemistry"],"published-print":{"date-parts":[[2026,12]]},"DOI":"10.1016\/j.ejmech.2026.119215","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:06:22Z","timestamp":1786374382000},"page":"119215","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"special_numbering":"C","title":["Discovery of 2, 4-disubstituted pyrimidine derivatives as selective HIPK2 inhibitors for potential treatment of chronic kidney disease"],"prefix":"10.1016","volume":"319","author":[{"given":"Xinlan","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyi","family":"Ouyang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengmeng","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianbin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"5","key":"10.1016\/j.ejmech.2026.119215_bib1","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.kint.2023.05.013","article-title":"Trends and perspectives for improving quality of chronic kidney disease care: conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference","volume":"104","author":"Eckardt","year":"2023","journal-title":"Kidney Int."},{"issue":"10440","key":"10.1016\/j.ejmech.2026.119215_bib2","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1016\/S0140-6736(24)00685-8","article-title":"Burden of disease scenarios for 204 countries and territories, 2022-2050: a forecasting analysis for the global burden of disease study 2021","volume":"403","year":"2024","journal-title":"Lancet"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/s41392-023-01379-7","article-title":"Kidney fibrosis: from mechanisms to therapeutic medicines","volume":"8","author":"Huang","year":"2023","journal-title":"Signal Transduct. Targeted Ther."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119215_bib4","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.7150\/ijbs.71595","article-title":"Smad3 signatures in renal inflammation and fibrosis","volume":"18","author":"Wu","year":"2022","journal-title":"Int. J. Biol. Sci."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119215_bib5","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41581-025-00934-5","article-title":"Advances and challenges in kidney fibrosis therapeutics","volume":"21","author":"Abbad","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"issue":"9","key":"10.1016\/j.ejmech.2026.119215_bib6","doi-asserted-by":"crossref","first-page":"Itc129","DOI":"10.7326\/ANNALS-25-02684","article-title":"Chronic kidney disease","volume":"178","author":"Grams","year":"2025","journal-title":"Ann. Intern. Med."},{"issue":"17","key":"10.1016\/j.ejmech.2026.119215_bib7","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.136004","article-title":"Tubular HIPK2 is a key contributor to renal fibrosis","volume":"5","author":"Xiao","year":"2020","journal-title":"JCI Insight"},{"issue":"4","key":"10.1016\/j.ejmech.2026.119215_bib8","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nm.2685","article-title":"A systems approach identifies HIPK2 as a key regulator of kidney fibrosis","volume":"18","author":"Jin","year":"2012","journal-title":"Nat. Med."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib9","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/kisup.2014.18","article-title":"Role of HIPK2 in kidney fibrosis","volume":"4","author":"Fan","year":"2014","journal-title":"Kidney Int. Suppl."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib10","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s41420-025-02916-9","article-title":"The homeodomain-interacting protein kinase hipk promotes apoptosis by stabilizing the active form of Dronc","volume":"12","author":"Garc\u00eda-Arias","year":"2025","journal-title":"Cell Death Discov."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib11","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1007\/s12265-023-10405-6","article-title":"HIPK1: a new druggable kinase target for treating pathological cardiac hypertrophy","volume":"17","author":"Spanos","year":"2024","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"10.1016\/j.ejmech.2026.119215_bib12","doi-asserted-by":"crossref","first-page":"7459","DOI":"10.2147\/OTT.S166878","article-title":"The expression level and prognostic value of HIPK3 among non-small-cell lung cancer patients in China","volume":"11","author":"Liu","year":"2018","journal-title":"OncoTargets Ther."},{"issue":"2","key":"10.1016\/j.ejmech.2026.119215_bib13","doi-asserted-by":"crossref","DOI":"10.1016\/j.isci.2024.108955","article-title":"Exosomal miR-3174 induced by hypoxia promotes angiogenesis and metastasis of hepatocellular carcinoma by inhibiting HIPK3","volume":"27","author":"Yang","year":"2024","journal-title":"iScience"},{"issue":"3","key":"10.1016\/j.ejmech.2026.119215_bib14","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.kint.2017.01.018","article-title":"The antihelmenthic phosphate niclosamide impedes renal fibrosis by inhibiting homeodomain-interacting protein kinase 2 expression","volume":"92","author":"Chang","year":"2017","journal-title":"Kidney Int."},{"issue":"7","key":"10.1016\/j.ejmech.2026.119215_bib15","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1681\/ASN.2016080841","article-title":"A novel inhibitor of homeodomain interacting protein kinase 2 mitigates kidney fibrosis through inhibition of the TGF-\u03b21\/Smad3 pathway","volume":"28","author":"Liu","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119215_bib16","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1681\/ASN.0000000000000327","article-title":"Small molecule allosteric inhibitor of HIPK2 as a novel therapy against kidney fibrosis","volume":"35","author":"Lee","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"10.1016\/j.ejmech.2026.119215_bib17","doi-asserted-by":"crossref","DOI":"10.1016\/j.ebiom.2022.104274","article-title":"Inhibition of HIPK2 protects stress-induced pathological cardiac remodeling","volume":"85","author":"Zhou","year":"2022","journal-title":"EBioMedicine"},{"issue":"8","key":"10.1016\/j.ejmech.2026.119215_bib18","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.bmcl.2018.03.018","article-title":"Discovery of 2,6-disubstituted pyrazine derivatives as inhibitors of CK2 and PIM kinases","volume":"28","author":"Gingipalli","year":"2018","journal-title":"Bioorg. Med. Chem. Lett"},{"issue":"4","key":"10.1016\/j.ejmech.2026.119215_bib19","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1021\/ml200257n","article-title":"Potent and selective inhibitors of CK2 kinase identified through structure-guided hybridization","volume":"3","author":"Dowling","year":"2012","journal-title":"ACS Med. Chem. Lett."},{"issue":"18","key":"10.1016\/j.ejmech.2026.119215_bib20","doi-asserted-by":"crossref","first-page":"15813","DOI":"10.1074\/jbc.M201075200","article-title":"STO-609, a specific inhibitor of the Ca(2+)\/calmodulin-dependent protein kinase kinase","volume":"277","author":"Tokumitsu","year":"2002","journal-title":"J. Biol. Chem."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib21","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2337\/dc16-0621","article-title":"Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial","volume":"40","author":"Mosenzon","year":"2017","journal-title":"Diabetes Care"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib22","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1097\/MNH.0000000000000556","article-title":"Nuclear factor erythroid 2-related factor 2 as a treatment target of kidney diseases","volume":"29","author":"Ito","year":"2020","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"10.1016\/j.ejmech.2026.119215_bib23","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2021.113299","article-title":"Highly selective inhibitors of protein kinases CLK and HIPK with the furo[3,2-b]pyridine core","volume":"215","author":"N\u011bmec","year":"2021","journal-title":"Eur. J. Med. Chem."},{"issue":"37","key":"10.1016\/j.ejmech.2026.119215_bib24","doi-asserted-by":"crossref","first-page":"13560","DOI":"10.1074\/jbc.H119.010675","article-title":"The long-awaited structure of HIPK2","volume":"294","author":"Murphy","year":"2019","journal-title":"J. Biol. Chem."},{"issue":"11","key":"10.1016\/j.ejmech.2026.119215_bib25","doi-asserted-by":"crossref","DOI":"10.3390\/ph17111420","article-title":"Virtual screening, molecular dynamics, and mechanism study of homeodomain-interacting protein kinase 2 inhibitor in renal fibroblasts","volume":"17","author":"Hu","year":"2024","journal-title":"Pharmaceuticals"},{"key":"10.1016\/j.ejmech.2026.119215_bib26","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmc.2025.118456","article-title":"Design, synthesis, and in vitro anti-renal fibrotic effects of imidazopyridazine-based homeodomain-interacting protein kinase 2 inhibitors","volume":"132","author":"Yao","year":"2026","journal-title":"Bioorg. Med. Chem."},{"key":"10.1016\/j.ejmech.2026.119215_bib27","doi-asserted-by":"crossref","DOI":"10.1016\/j.cbi.2025.111771","article-title":"Fragment-based discovery, dynamics simulation and pharmacological study of 2-amino-pyrimidine derivative as HIPK2 inhibitor","volume":"421","author":"Wu","year":"2025","journal-title":"Chem. Biol. Interact."},{"key":"10.1016\/j.ejmech.2026.119215_bib28","doi-asserted-by":"crossref","DOI":"10.1016\/j.bioorg.2022.105866","article-title":"Identification of selective homeodomain interacting protein kinase 2 inhibitors, a potential treatment for renal fibrosis","volume":"126","author":"Hu","year":"2022","journal-title":"Bioorg. Chem."},{"issue":"Pt 2","key":"10.1016\/j.ejmech.2026.119215_bib29","article-title":"Discovery of XRF-1021, a 2,4-disubstituted-5-fluoropyrimidine derivative as a homeodomain-interacting protein kinase 2 inhibitor for the treatment of chronic kidney disease","volume":"302","author":"Hu","year":"2026","journal-title":"Eur. J. Med. Chem."},{"issue":"12","key":"10.1016\/j.ejmech.2026.119215_bib30","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nrm3904","article-title":"Remodelling the extracellular matrix in development and disease","volume":"15","author":"Bonnans","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"1\u20132","key":"10.1016\/j.ejmech.2026.119215_bib31","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cytogfr.2005.09.008","article-title":"Smad3 is key to TGF-beta-mediated epithelial-to-mesenchymal transition, fibrosis, tumor suppression and metastasis","volume":"17","author":"Roberts","year":"2006","journal-title":"Cytokine Growth Factor Rev."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib32","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/ncb714","article-title":"Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis","volume":"4","author":"D'Orazi","year":"2002","journal-title":"Nat. Cell Biol."},{"issue":"5","key":"10.1016\/j.ejmech.2026.119215_bib33","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1038\/s41419-024-06702-w","article-title":"Targeting tumor suppressor p53 for organ fibrosis therapy","volume":"15","author":"Bao","year":"2024","journal-title":"Cell Death Dis."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib34","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/ncb1816","article-title":"An inducible autoregulatory loop between HIPK2 and Siah2 at the apex of the hypoxic response","volume":"11","author":"Calzado","year":"2009","journal-title":"Nat. Cell Biol."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119215_bib35","doi-asserted-by":"crossref","DOI":"10.1111\/acel.70546","article-title":"Tubular Omega-3 fatty acid receptor FFAR4 deficiency aggravated renal aging and chronic kidney disease","volume":"25","author":"Yang","year":"2026","journal-title":"Aging Cell"},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib36","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1038\/s41401-023-01156-w","article-title":"Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis","volume":"45","author":"Wang","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"issue":"38","key":"10.1016\/j.ejmech.2026.119215_bib37","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2505752122","article-title":"Tubular ACSM3 deficiency impairs medium-chain fatty acid metabolism and aggravates kidney fibrosis","volume":"122","author":"Li","year":"2025","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"1","key":"10.1016\/j.ejmech.2026.119215_bib38","doi-asserted-by":"crossref","first-page":"3200","DOI":"10.1038\/s41467-024-47315-3","article-title":"Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1\u03b2-dependent macrophage activation and tubular cell senescence","volume":"15","author":"Li","year":"2024","journal-title":"Nat. Commun."},{"key":"10.1016\/j.ejmech.2026.119215_bib39","doi-asserted-by":"crossref","DOI":"10.1016\/j.biopha.2020.110949","article-title":"Contribution of TFEB-mediated autophagy to tubulointerstitial fibrosis in mice with adenine-induced chronic kidney disease","volume":"133","author":"Yuan","year":"2021","journal-title":"Biomed. Pharmacother."},{"issue":"W1","key":"10.1016\/j.ejmech.2026.119215_bib40","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"issue":"6","key":"10.1016\/j.ejmech.2026.119215_bib41","doi-asserted-by":"crossref","first-page":"2869","DOI":"10.1016\/j.apsb.2021.12.012","article-title":"Nuciferine protects against high-fat diet-induced hepatic steatosis and insulin resistance via activating TFEB-mediated autophagy-lysosomal pathway","volume":"12","author":"Du","year":"2022","journal-title":"Acta Pharm. Sin. B"}],"container-title":["European Journal of Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426006604?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0223523426006604?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T15:04:14Z","timestamp":1793977454000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0223523426006604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,12]]},"references-count":41,"alternative-id":["S0223523426006604"],"URL":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119215","relation":{},"ISSN":["0223-5234"],"issn-type":[{"value":"0223-5234","type":"print"}],"subject":[],"published":{"date-parts":[[2026,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Discovery of 2, 4-disubstituted pyrimidine derivatives as selective HIPK2 inhibitors for potential treatment of chronic kidney disease","name":"articletitle","label":"Article Title"},{"value":"European Journal of Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejmech.2026.119215","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"119215"}}