{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:43:13Z","timestamp":1792806193186,"version":"4.5.0"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Major Scientific and Technological Special Project for \u201cSignificant New Drug Development\u201d","award":["2014ZX09507007-003"],"award-info":[{"award-number":["2014ZX09507007-003"]}]},{"name":"National Major Scientific and Technological Special Project for \u201cSignificant New Drug Development\u201d","award":["21771022"],"award-info":[{"award-number":["21771022"]}]},{"name":"National Major Scientific and Technological Special Project for \u201cSignificant New Drug Development\u201d","award":["U1804188"],"award-info":[{"award-number":["U1804188"]}]},{"name":"National Natural Science Foundation of China","award":["2014ZX09507007-003"],"award-info":[{"award-number":["2014ZX09507007-003"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["21771022"],"award-info":[{"award-number":["21771022"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Natural Science Foundation of China","award":["U1804188"],"award-info":[{"award-number":["U1804188"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: KRAS-G12D mutations drive 20\u201350% of pancreatic\/biliary cancers yet remain challenging to target due to GTP-pocket conservation and high cellular GTP levels. While allosteric inhibitors targeting the SWII pocket (e.g., MRTX1133) show promise, limited chemical diversity and paradoxical cellular\/enzymatic activity relationships necessitate the exploration of novel scaffolds. This study aims to develop KRAS-G12D inhibitors and PROTACs to offer a selection of new chemical entities through systematic structure\u2013activity optimization and evaluate their therapeutic potential through PROTAC derivatization. Methods: Eleven compounds featuring heterocyclic cores (pyrimidine\/pyrido[4,3-d]pyrimidine\/5,6,7,8-tetrahydroprodo[3,4-d]pyrimidine) were designed via structure-based drug design. Antiproliferative activity against KRAS-G12D (Panc1), KRAS-G13D (HCT116) and wild-type (A549) cells was assessed using the CCK-8 assay. KRAS-G12D enzymatic inhibition was measured using a GTPase activity assay. Molecular docking simulations (Sybyl 2.0; PDB:7RPZ) elucidated binding modes. Two PROTACs were synthesized from lead compounds by conjugating E3 ligase linkers. All the novel inhibitors and PROTACs were characterized by means of NMR or HRMS. Results: Compound 10c demonstrated selective anti-proliferation in Panc1 cells (IC50 = 1.40 \u03bcM) with 4.9-fold greater selectivity over wild-type cells, despite weak enzymatic inhibition (IC50 &gt; 10 \u03bcM). Docking revealed critical hydrogen bonds between its protonated 3,8-diazabicyclo[3.2.1]octane moiety and Asp12\/Gly60. The enzymatic inhibitor 10k showed potent KRAS-G12D inhibition (IC50 = 0.009 \u03bcM) through homopiperazine-mediated interactions with Glu92\/His95. Derived PROTACs 26a\/b exhibited reduced potency (IC50 = 3\u20135 \u03bcM vs. parental 10k: 2.22 \u03bcM), potentially due to impaired membrane permeability. Conclusions: Eleven novel KRAS-G12D inhibitors with a seven-membered ring pharmacophore were synthesized. Compound 10c showed strong anti-proliferative activity, while 10k exhibited potent enzymatic inhibition. Two PROTACs were designed but showed no clear advantage over 10k. This study provides valuable insights for KRAS-targeted drug development.<\/jats:p>","DOI":"10.3390\/ph18050696","type":"journal-article","created":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T11:37:02Z","timestamp":1746704222000},"page":"696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design, Synthesis, Anticancer Evaluation and Molecular Docking of Pyrimidine, Pyrido[4,3-d]pyrimidine and 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidine Derivatives as Novel KRAS-G12D Inhibitors and PROTACs"],"prefix":"10.3390","volume":"18","author":[{"given":"Hailong","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Radiopharmaceuticals of the Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Gan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Radiopharmaceuticals of the Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huabei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Radiopharmaceuticals of the Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.apsb.2019.03.002","article-title":"Targeting the untargetable KRAS in cancer therapy","volume":"9","author":"Liu","year":"2019","journal-title":"Acta Pharm. 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