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The clinical therapeutic benefits of the second\u2010generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent\u2010front mutations (e.g., RET\n                    <jats:sup>G810R\/S\/C<\/jats:sup>\n                    ). Herein, a class of 2\u2010aminopyrazolpyrimidopyridone derivatives as RET\n                    <jats:sup>V804M<\/jats:sup>\n                    and RET\n                    <jats:sup>G810C<\/jats:sup>\n                    solvent\u2010front mutant inhibitors were designed and synthesized for overcoming pralsetinib resistance. One of the optimal compounds,\n                    <jats:bold>7la<\/jats:bold>\n                    , exhibited inhibitory potency against the proliferation of BaF3 cells harboring CCDC6\u2010RET\n                    <jats:sup>V804M<\/jats:sup>\n                    mutation with IC50 values of 0.271\u2009\u03bcM. Interestingly, another one of these series compounds,\n                    <jats:bold>7qe<\/jats:bold>\n                    , suppressed BaF3 cells harboring CCDC6\u2010RET\n                    <jats:sup>V804M<\/jats:sup>\n                    and CCDC6\u2010RET\n                    <jats:sup>G810C<\/jats:sup>\n                    mutations with IC\n                    <jats:sub>50<\/jats:sub>\n                    values of 0.841 and 0.272\u2009\u03bcM, respectively. The compound also dose\u2010dependently suppressed the activation of RET and downstream signals. However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound\n                    <jats:bold>7qe<\/jats:bold>\n                    might be a promising lead compound 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 clinical acquired resistance.\n                  <\/jats:p>","DOI":"10.1111\/cbdd.70191","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:33:06Z","timestamp":1761895986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design and Synthesis of 2\u2010Aminopyrazolpyrimidopyridone Derivatives as\n                    <scp>\n                      RET\n                      <sup>V<\/sup>\n                    <\/scp>\n                    <sup>\n                      804\n                      <scp>M<\/scp>\n                    <\/sup>\n                    and\n                    <scp>\n                      RET\n                      <sup>G<\/sup>\n                    <\/scp>\n                    <sup>\n                      810\n                      <scp>C<\/scp>\n                    <\/sup>\n                    Kinase Inhibitors"],"prefix":"10.1111","volume":"106","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":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anzhi","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieman","family":"Lin","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihu","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyu","family":"Jia","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry Gannan Normal University  Ganzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangxi Chiralsyn Biological 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