{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:25Z","timestamp":1787013985860,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004479","name":"Natural Science Foundation of Jiangxi Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004479","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Chem Biol Drug Des"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    RET (Rearranged during transfection) kinase is a validated target for non\u2010small cell lung cancer (NSCLC). In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, high treatment costs and clinically acquired resistance (e.g., G810C\/S\/R) become the new challenges for RET\u2010based therapies. In this work, we discovered a series of 2\u2010aminopyrazolpyrimidopyridone RET inhibitors to overcome the V804M and G810C resistant mutations. One of the compounds,\n                    <jats:bold>8w<\/jats:bold>\n                    , exhibited inhibitory potency against the BaF3 cells harboring CCDC6\u2010RET\n                    <jats:sup>V804M<\/jats:sup>\n                    mutation with an IC50 value of 0.715\u2009\u03bcM. The compound also dose\u2010dependently suppressed the activation of RET and downstream signals. Another compound,\n                    <jats:bold>8s<\/jats:bold>\n                    suppressed BaF3 cells harboring CCDC6\u2010RET\n                    <jats:sup>G810C<\/jats:sup>\n                    mutation with an IC\n                    <jats:sub>50<\/jats:sub>\n                    value of 2.91\u2009\u03bcM. However, the poor solubility of these compounds will limit their further development. Therefore, compound\n                    <jats:bold>8w<\/jats:bold>\n                    and\n                    <jats:bold>8s<\/jats:bold>\n                    might be promising lead compounds for the development of novel RET\n                    <jats:sup>V804M<\/jats:sup>\n                    and RET\n                    <jats:sup>G810C<\/jats:sup>\n                    inhibitors overcoming the clinically acquired resistance.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70039","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T20:39:46Z","timestamp":1735591186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structure\u2010Based Design of 2\u2010Aminopyrazolpyrimidopyridone Derivatives as New Rearranged During Transfection (\n                    <scp>RET<\/scp>\n                    ) Kinase Inhibitors"],"prefix":"10.1111","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5604-7973","authenticated-orcid":false,"given":"Jiayi","family":"Shen","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihu","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Tan","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangxi ChiralSyn Biological Medicine Co. Ltd  Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongdong","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)60421-9"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.175"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30562-9"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz244.068"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.48.4659"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13051091"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.3279"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2019.09.011"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2021-1464"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw559"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2016.04.076"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2021.102153"},{"key":"e_1_2_7_14_1","volume-title":"Condensed Pyrimidine Compound or Salt Thereof","author":"Miyazaki I.","year":"2017"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95612-4"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.12798"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00576"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.01.006"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1116"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0338"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.10.599"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy137"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.02551"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(85)90115-1"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00216"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.35.5040"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/C5MD00208G"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01280"}],"container-title":["Chemical Biology &amp; Drug Design"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cbdd.70039","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,13]],"date-time":"2025-04-13T07:13:19Z","timestamp":1744528399000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cbdd.70039"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,30]]},"references-count":27,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["10.1111\/cbdd.70039"],"URL":"https:\/\/doi.org\/10.1111\/cbdd.70039","archive":["Portico"],"relation":{},"ISSN":["1747-0277","1747-0285"],"issn-type":[{"value":"1747-0277","type":"print"},{"value":"1747-0285","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,30]]},"assertion":[{"value":"2024-09-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70039"}}