{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:54:41Z","timestamp":1787237681129,"version":"build-2736575974"},"reference-count":114,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>For decades RAS mutations represented a chimera for drug developers, as all efforts put into attempting to pharmacologically inhibit them failed. Finally, in recent years, the advent of the KRAS G12C inhibitors sotorasib and adagrasib pushed the development of several new drugs; therefore, the landscape of RAS inhibitors evolved and now includes several compounds with different mechanisms of action. In this review we provide an updated summary of RAS inhibitor drugs, detailing their mechanism of action, pharmacokinetics and toxicity profile as well as efficacy studies.<\/jats:p>","DOI":"10.3390\/pharmaceutics18070773","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:52:11Z","timestamp":1782453131000},"page":"773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["RAS Inhibitors: Changing the Paradigm from the Undruggable"],"prefix":"10.3390","volume":"18","author":[{"given":"Federica","family":"Campana","sequence":"first","affiliation":[{"name":"Department of Human, Philosophical and Formation Sciences, University of Salerno, 84084 Fisciano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"De Bellis","sequence":"additional","affiliation":[{"name":"PhD School \u201cClinical and Translational Oncology (CTO)\u201d, Scuola Superiore Meridionale, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3997-5913","authenticated-orcid":false,"given":"Floriana","family":"Porcaro","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Di Guida","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Della Gravara","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-224X","authenticated-orcid":false,"given":"Alberto","family":"Servetto","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine and Surgery, University of Naples \u201cFederico II\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"Morgillo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-8696","authenticated-orcid":false,"given":"Federica","family":"Papaccio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy"},{"name":"Clinical Pharmacology Unit, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84100 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8235-9118","authenticated-orcid":false,"given":"Amelia","family":"Filippelli","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy"},{"name":"Clinical Pharmacology Unit, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84100 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-8099","authenticated-orcid":false,"given":"Carminia Maria","family":"Della Corte","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6964-2739","authenticated-orcid":false,"given":"Valeria","family":"Conti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, 84081 Baronissi, Italy"},{"name":"Clinical Pharmacology Unit, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84100 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1080\/13543776.2022.2032648","article-title":"Inhibitors of the GTPase KRASG12C in cancer: A patent review (2019\u20132021)","volume":"32","author":"Xu","year":"2022","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"346","DOI":"10.21037\/tlcr-22-639","article-title":"Targeted therapies for KRAS-mutant non-small cell lung cancer: From preclinical studies to clinical development-a narrative review","volume":"12","author":"Santarpia","year":"2023","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.21037\/tlcr-2025-164","article-title":"Literature review of advances and challenges in KRASG12C mutant non-small cell lung cancer","volume":"14","author":"Yuan","year":"2025","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.ccell.2026.01.001","article-title":"Emerging landscape of KRAS inhibitors in cancer treatment","volume":"44","author":"Riedl","year":"2026","journal-title":"Cancer Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.3390\/curroncol31040150","article-title":"KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance","volume":"31","author":"Ash","year":"2024","journal-title":"Curr. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1002\/cac2.70056","article-title":"Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I\/II trials","volume":"45","author":"Li","year":"2025","journal-title":"Cancer Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1007\/s40265-024-02030-7","article-title":"Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments","volume":"84","author":"Espinar","year":"2024","journal-title":"Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/s41401-023-01194-4","article-title":"From bench to bedside: Current development and emerging trend of KRAS-targeted therapy","volume":"45","author":"Chen","year":"2024","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s40265-021-01574-2","article-title":"Sotorasib: First Approval","volume":"81","author":"Blair","year":"2021","journal-title":"Drugs"},{"key":"ref_10","unstructured":"(2026, April 07). LUMAKRASTM (sotorasib) Tablets, for Oral Use: US Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2025\/214665Orig1s009correctedlbl.pdf."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.1158\/1538-7445.AM2019-4484","article-title":"Abstract 4484: Discovery and in vitro characterization of AMG 510\u2013a potent and selective covalent small-molecule inhibitor of KRASG12C","volume":"79","author":"Saiki","year":"2019","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1158\/2159-8290.CD-22-0158","article-title":"Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C","volume":"12","author":"Weiss","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.1080\/14796694.2024.2407280","article-title":"An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer","volume":"20","author":"Tenekeci","year":"2024","journal-title":"Future Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1158\/2159-8290.CD-19-1167","article-title":"The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients","volume":"10","author":"Hallin","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s40265-023-01839-y","article-title":"Adagrasib: First Approval","volume":"83","author":"Dhillon","year":"2023","journal-title":"Drugs"},{"key":"ref_16","unstructured":"(2026, April 07). KRAZATITM (adagrasib) Tablets, for Oral Use: US Prescribing Information, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/216340s000lbl.pdf."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s11523-024-01055-y","article-title":"Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC","volume":"19","author":"Brazel","year":"2024","journal-title":"Target. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1056\/NEJMoa2303810","article-title":"Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation","volume":"389","author":"Sacher","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102668","DOI":"10.1016\/j.tranon.2026.102668","article-title":"Advances on drug therapy for KRASG12C-mutant non-small-cell lung cancer","volume":"65","author":"Tian","year":"2026","journal-title":"Transl. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s41392-025-02315-7","article-title":"Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRASG12C inhibitor-na\u00efve Chinese patients with KRASG12C-mutated metastatic colorectal cancer: A pooled analysis from phase I part of two studies","volume":"10","author":"Yuan","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"114337","DOI":"10.1016\/j.ejca.2024.114337","article-title":"Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: First-in-human phase I study","volume":"212","author":"Zhou","year":"2024","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.jtho.2023.03.015","article-title":"D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRASG12C in Patients with NSCLC: Phase 1 Study Results","volume":"18","author":"Li","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1200\/JCO.2022.40.16_suppl.3089","article-title":"A phase I\/II study of first-in-human trial of JAB-21822 (KRAS G12C inhibitor) in advanced solid tumors","volume":"40","author":"Li","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6041","DOI":"10.1021\/acs.jmedchem.4c02313","article-title":"Discovery of Elironrasib (RMC-6291), a Potent and Orally Bioavailable, RAS(ON) G12C-Selective, Covalent Tricomplex Inhibitor for the Treatment of Patients with RAS G12C-Addicted Cancers","volume":"68","author":"Cregg","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_25","unstructured":"(2026, April 02). Olomorasib (KRAS G12C Inhibitor 19) | KRAS G12C Inhibitor | MedChemExpress. Available online: https:\/\/www.medchemexpress.com\/kras-g12c-inhibitor-19.html."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1158\/0008-5472.CAN-25-0600","article-title":"RAS-GTP Inhibition Overcomes Acquired Resistance to KRASG12C Inhibitors Mediated by Oncogenic and Wild-Type RAS Activation in Non-Small Cell Lung Cancer","volume":"86","author":"Solanki","year":"2026","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"PR014","DOI":"10.1158\/1535-7163.TARG-23-PR014","article-title":"Abstract PR014: Preliminary safety and anti-tumor activity of RMC-6291, a first-in-class, tri-complex KRASG12C(ON) inhibitor, in patients with or without prior KRASG12C(OFF) inhibitor treatment","volume":"22","author":"Bigot","year":"2023","journal-title":"Mol. Cancer Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1158\/2159-8290.CD-24-0840","article-title":"Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C","volume":"15","author":"Maciag","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6064","DOI":"10.1021\/acs.jmedchem.4c02314","article-title":"Discovery of Daraxonrasib (RMC-6236), a Potent and Orally Bioavailable RAS(ON) Multi-selective, Noncovalent Tri-complex Inhibitor for the Treatment of Patients with Multiple RAS-Addicted Cancers","volume":"68","author":"Cregg","year":"2025","journal-title":"J. Med. Chem."},{"key":"ref_30","first-page":"762","article-title":"Drugging the \u2018undruggable\u2019 KRAS: Breakthroughs, challenges, and opportunities in pancreatic cancer","volume":"22","author":"Khan","year":"2025","journal-title":"Cancer Biol. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e70203","DOI":"10.1111\/1759-7714.70203","article-title":"Targeting KRAS G12D: Advances in Inhibitor Design","volume":"16","author":"Shi","year":"2025","journal-title":"Thorac. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1038\/s41591-022-02007-7","article-title":"Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor","volume":"28","author":"Hallin","year":"2022","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1158\/2159-8290.CD-22-1066","article-title":"Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer","volume":"13","author":"Kemp","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3123","DOI":"10.1021\/acs.jmedchem.1c01688","article-title":"Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor","volume":"65","author":"Wang","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_35","unstructured":"Mirati Therapeutics Inc. (2026, April 07). A Phase 1\/2 Multiple Expansion Cohort Trial of MRTX1133 in Patients with Advanced Solid Tumors Harboring a KRAS G12D Mutation, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05737706."},{"key":"ref_36","unstructured":"(2026, April 07). Bristol Exits KRAS G12D. ApexOnco. Available online: https:\/\/www.apexonco.com\/bristol-exits-kras-g12d."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1158\/2159-8290.CD-25-1346","article-title":"Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRAS G12D Inhibitor","volume":"16","author":"Xie","year":"2026","journal-title":"Cancer Discov."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1200\/JCO.2026.44.2_suppl.729","article-title":"A phase 1, first-in-human, open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of RNK08954 in patients with advanced solid tumors with a KRAS G12D mutation","volume":"44","author":"Ying","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1016\/j.ccell.2024.06.001","article-title":"Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer","volume":"42","author":"Zhou","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_40","unstructured":"Jiangsu HengRui Medicine Co., Ltd. (2026, April 07). Phase I Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of HRS-4642 in Patients with Advanced Solid Tumors Harboring KRAS G12D Mutation, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05533463."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"S1273","DOI":"10.1016\/j.annonc.2023.10.025","article-title":"LBA33 A first-in-human phase I study of a novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors harboring KRAS G12D mutation","volume":"34","author":"Zhou","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S558","DOI":"10.1016\/j.annonc.2025.08.1484","article-title":"915O KRAS G12D inhibitor HRS-4642 in patients with KRAS G12D-mutant advanced solid tumors: A phase I trial","volume":"36","author":"Xiong","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"eads0239","DOI":"10.1126\/science.ads0239","article-title":"A neomorphic protein interface catalyzes covalent inhibition of RASG12D aspartic acid in tumors","volume":"389","author":"Weller","year":"2025","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1158\/2159-8290.CD-25-0679","article-title":"A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer","volume":"16","author":"Centonze","year":"2026","journal-title":"Cancer Discov."},{"key":"ref_45","unstructured":"(2026, April 02). Cancer Interception with KRAS Inhibitors in Preclinical Models of Pancreatic Ductal Adenocarcinoma | Science. Available online: https:\/\/www.science.org\/doi\/10.1126\/science.aec7929."},{"key":"ref_46","unstructured":"Revolution Medicines, Inc. (2026, April 08). Phase 1\/1b, Multicenter, Open-Label, Study of RMC 9805 in Participants with Advanced KRASG 12D-Mutant Solid Tumors, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06040541."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"CT019","DOI":"10.1158\/1538-7445.AM2025-CT019","article-title":"Abstract CT019: Preliminary safety and antitumor activity of zoldonrasib (RMC-9805), an oral, RAS(ON) G12D-selective, tri-complex inhibitor in patients with KRAS G12D non-small cell lung cancer (NSCLC) from a phase 1 study in advanced solid tumors","volume":"85","author":"Arbour","year":"2025","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1200\/JCO.2025.43.4_suppl.724","article-title":"Abstract 724: Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors","volume":"43","author":"Spira","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5900","DOI":"10.1158\/1538-7445.AM2024-5900","article-title":"Abstract 5900: INCB161734: A novel, potent, and orally bioavailable KRAS G12D selective inhibitor demonstrates antitumor activity in KRAS G12D mutant tumors","volume":"84","author":"Farren","year":"2024","journal-title":"Cancer Res."},{"key":"ref_50","unstructured":"Incyte Corporation (2026, April 08). A Phase 1, Open-Label, Multicenter Study of INCB161734 in Participants with Advanced or Metastatic Solid Tumors with KRAS G12D Mutation, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06179160."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"S559","DOI":"10.1016\/j.annonc.2025.08.1485","article-title":"Abstract 916O: Preliminary phase I results of INCB161734, a novel oral KRAS G12D inhibitor, in patients with advanced or metastatic solid tumors","volume":"36","author":"Desai","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1200\/JCO.2026.44.2_suppl.654","article-title":"Preliminary phase 1 results of INCB161734, a novel oral Kirsten rat sarcoma (KRAS) G12D inhibitor, as monotherapy or in combination with chemotherapy for advanced\/metastatic pancreatic duct adenocarcinoma (PDAC)","volume":"44","author":"Wainberg","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_53","unstructured":"Genfleet Therapeutics (Shanghai) Inc. (2026, April 08). An Open-Label, Phase I\/II Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of GFH375 in Patients with KRAS G12D Mutant Advanced Solid Tumors, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06500676."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1200\/JCO.2025.43.16_suppl.3013","article-title":"A first-in-human phase I\/II study of GFH375, a highly selective and potent oral KRAS G12D inhibitor in patients with KRAS G12D mutant advanced solid tumors","volume":"43","author":"Ai","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"S1626","DOI":"10.1016\/j.annonc.2025.09.099","article-title":"Abstract LBA84: Efficacy and safety of GFH375 monotherapy in previously treated advanced KRAS G12D-mutant pancreatic ductal adenocarcinoma (PDAC)","volume":"36","author":"Zhou","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1200\/JCO.2025.43.16_suppl.3083","article-title":"The first-in-human phase 1\/2 study of TSN1611, a highly selective KRAS G12D inhibitor, in patients with advanced solid tumors","volume":"43","author":"Fu","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"ND11","DOI":"10.1158\/1538-7445.AM2025-ND11","article-title":"Abstract ND11: AZD0022: A potent, oral KRASG12D-selective inhibitor that drives robust pathway inhibition and anti-tumour activity in KRASG12D models","volume":"85","author":"Martins","year":"2025","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"TPS845","DOI":"10.1200\/JCO.2025.43.4_suppl.TPS845","article-title":"MOONRAY-01, a phase 1 study of LY3962673, a potent, orally bioavailable, and selective KRAS G12D inhibitor in KRAS G12D-mutant solid tumors","volume":"43","author":"Lakhani","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s42004-025-01662-4","article-title":"Discovery of KRAS(G12D) selective degrader ASP3082","volume":"8","author":"Yoshinari","year":"2025","journal-title":"Commun. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"S486","DOI":"10.1016\/j.annonc.2024.08.675","article-title":"Abstract 608O: Preliminary safety and clinical activity of ASP3082, a first-in-class, KRAS G12D selective protein degrader in adults with advanced pancreatic (PC), colorectal (CRC), and non-small cell lung cancer (NSCLC)","volume":"35","author":"Park","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1200\/JCO.2026.44.2_suppl.704","article-title":"Abstract 704: Efficacy and safety of ASP3082 monotherapy or in combination with mFOLFIRINOX in patients (pts) with pancreatic ductal adenocarcinoma (PDAC)","volume":"44","author":"Kasi","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1158\/2159-8290.CD-24-0027","article-title":"Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers","volume":"14","author":"Jiang","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"S458","DOI":"10.1016\/j.annonc.2023.09.1838","article-title":"Abstract 652O: Preliminary clinical activity of RMC-6236, a first-in-class, RAS-selective, tri-complex RAS-MULTI(ON) inhibitor in patients with KRAS mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC)","volume":"34","author":"Arbour","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1021\/acs.jmedchem.1c01774","article-title":"Discovery of the First-in-Class Agonist-Based SOS1 PROTACs Effective in Human Cancer Cells Harboring Various KRAS Mutations","volume":"65","author":"Zhou","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"S591","DOI":"10.1016\/j.annonc.2021.08.1046","article-title":"Abstract 524P: A phase I.; open-label, dose-escalation trial of BI 1701963 in patients (pts) with KRAS mutated solid tumours: A snapshot analysis","volume":"32","author":"Johnson","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"ND01","DOI":"10.1158\/1538-7445.AM2025-ND01","article-title":"Abstract ND01: AMG 410: An H\/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)\/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors","volume":"85","author":"Lanman","year":"2025","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1158\/1538-7445.AM2025-390","article-title":"Abstract 390: ERAS-0015 is a pan-RAS molecular glue with best-in-class potential in RAS mutant solid tumors","volume":"85","author":"Lew","year":"2025","journal-title":"Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View\u2014Molecular graphics for all devices\u2014From smartphones to workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41573-020-0068-6","article-title":"RAS-targeted therapies: Is the undruggable drugged?","volume":"19","author":"Moore","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/s41392-025-02473-8","article-title":"Targeting KRAS mutations: Orchestrating cancer evolution and therapeutic challenges","volume":"10","author":"Choucair","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"TPS8653","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS8653","article-title":"Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202)","volume":"42","author":"Barlesi","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2204619","article-title":"Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation","volume":"387","author":"Riely","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3318","DOI":"10.1158\/1078-0432.CCR-22-0383","article-title":"Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer","volume":"28","author":"Sabari","year":"2022","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0140-6736(25)00866-9","article-title":"Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): A randomised, open-label, phase 3 trial","volume":"406","author":"Barlesi","year":"2025","journal-title":"Lancet"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"S349","DOI":"10.1016\/j.jtho.2024.09.629","article-title":"Abstract P3.12D.07: Divarasib Versus Adagrasib or Sotorasib in Pretreated KRAS G12C+ Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)","volume":"19","author":"Gadgeel","year":"2024","journal-title":"J. Thorac. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"O\u2019Reilly, E.M., Wainberg, Z.A., Hendifar, A.E., Borad, M.J., Pietrantonio, F., Pant, S., Hammel, P., Cremolini, C., Manji, G.A., and Oberstein, P.E. (2026). Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. N. Engl. J. Med., Epub ahead of print.","DOI":"10.1056\/NEJMoa2605555"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.1016\/j.jtho.2022.07.025","article-title":"Abstract OA03.06: CodeBreaK 100\/101: First Report of Safety\/Efficacy of Sotorasib in Combination with Pembrolizumab or Atezolizumab in Advanced KRAS p.G12C NSCLC","volume":"17","author":"Li","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1200\/JCO.18.00149","article-title":"Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer with PD-L1 Tumor Proportion Score of 50% or Greater","volume":"37","author":"Reck","year":"2019","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"8500","DOI":"10.1200\/JCO.2025.43.16_suppl.8500","article-title":"Abstract 8500: First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced\/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) from the phase 2 portion of the KRYSTAL-7 study","volume":"43","author":"Theelen","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa2212419","article-title":"Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C","volume":"388","author":"Yaeger","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1200\/JCO-25-00040","article-title":"Single-Agent Divarasib in Patients with KRAS G12C-Positive Non-Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study","volume":"43","author":"Sacher","year":"2025","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"S121","DOI":"10.1016\/j.annonc.2021.05.126","article-title":"Abstract P-71: KRYSTAL-10: A randomized phase 3 study of adagrasib (MRTX849) in combination with cetuximab vs chemotherapy in patients with previously treated advanced colorectal cancer with KRASG12C mutation","volume":"32","author":"Tabernero","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41591-023-02696-8","article-title":"Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: A phase 1b trial","volume":"30","author":"Desai","year":"2024","journal-title":"Nat. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1200\/JCO-24-02026","article-title":"Overall Survival Analysis of the Phase III CodeBreaK 300 Study of Sotorasib Plus Panitumumab Versus Investigator\u2019s Choice in Chemorefractory KRAS G12C Colorectal Cancer","volume":"43","author":"Pietrantonio","year":"2025","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"S429","DOI":"10.1016\/j.annonc.2024.08.574","article-title":"505O Sotorasib (soto), panitumumab (pani) and FOLFIRI in the first-line (1L) setting for KRAS G12C\u2013mutated metastatic colorectal cancer (mCRC): Safety and efficacy analysis from the phase Ib CodeBreaK 101 study","volume":"35","author":"Siena","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_88","first-page":"TPS326","article-title":"A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C\u2013mutated metastatic colorectal cancer (CodeBreaK 301)","volume":"43","author":"Kim","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2208470","article-title":"Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer","volume":"388","author":"Strickler","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_90","unstructured":"(2026, April 08). Adagrasib (MRTX849) | KRAS G12C Inhibitor | MedChemExpress. Available online: https:\/\/www.medchemexpress.com\/mrtx849.html."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.trecan.2024.11.009","article-title":"KRAS inhibitors: Resistance drivers and combinatorial strategies","volume":"11","author":"Isermann","year":"2025","journal-title":"Trends Cancer"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1111\/cas.16441","article-title":"Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells\u2019 Strategic Use of Normal Cellular Mechanisms to Adapt","volume":"116","author":"Tanaka","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1158\/2159-8290.CD-25-0349","article-title":"Response and Resistance to RAS inhibition in Cancer","volume":"15","author":"Ebright","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1002\/1878-0261.70149","article-title":"The rapidly growing landscape of RAS inhibitors: From selective allele blockade to broad inhibition strategies","volume":"19","author":"Drosten","year":"2025","journal-title":"Mol. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"ND06","DOI":"10.1158\/1538-7445.AM2025-ND06","article-title":"Abstract ND06: Discovery of RMC-5127, an oral, RAS (ON) G12V-selective, noncovalent, tri-complex inhibitor","volume":"85","author":"Edwards","year":"2025","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.ccell.2025.05.016","article-title":"A first-in-class EGFR-directed KRAS G12V selective inhibitor","volume":"43","author":"Stanland","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1038\/s41467-021-22969-5","article-title":"Selective and noncovalent targeting of RAS mutants for inhibition and degradation","volume":"12","author":"Teng","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40164-025-00637-4","article-title":"New exploration of KRASG12D inhibitors and the mechanisms of resistance","volume":"14","author":"Li","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1158\/2159-8290.CD-24-0177","article-title":"Mechanisms of Resistance to Oncogenic KRAS Inhibition in Pancreatic Cancer","volume":"14","author":"Dilly","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41698-024-00793-6","article-title":"Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization","volume":"9","author":"Maruyama","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1158\/1535-7163.MCT-25-0483","article-title":"Resistance to the KRASG12D Inhibitor MRTX1133 is Associated with Increased Sensitivity to BET Inhibition","volume":"25","author":"Principe","year":"2026","journal-title":"Mol. Cancer Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1200\/JCO.22.02524","article-title":"Long-Term Outcomes and Molecular Correlates of Sotorasib Efficacy in Patients with Pretreated KRAS G12C-Mutated Non\u2013Small-Cell Lung Cancer: 2-Year Analysis of CodeBreaK 100","volume":"41","author":"Dy","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1158\/1078-0432.CCR-24-2948","article-title":"Identification of candidate alterations mediating KRAS G12C inhibitor resistance in advanced colorectal and pancreatic cancers","volume":"31","author":"Jazieh","year":"2025","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","article-title":"Acquired Resistance to KRASG12C Inhibition in Cancer","volume":"384","author":"Awad","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41586-021-04065-2","article-title":"Diverse alterations associated with resistance to KRAS(G12C) inhibition","volume":"599","author":"Zhao","year":"2021","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1158\/2159-8290.CD-21-0365","article-title":"Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation","volume":"11","author":"Tanaka","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_107","first-page":"1321","article-title":"KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments","volume":"16","author":"Koga","year":"2021","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Baldelli, E., El Gazzah, E., Moran, J.C., Hodge, K.A., Manojlovic, Z., Bassiouni, R., Carpten, J.D., Ludovini, V., Baglivo, S., and Crin\u00f2, L. (2021). Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas. Genes., 12.","DOI":"10.3390\/genes12091402"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1158\/1078-0432.CCR-19-3523","article-title":"Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition","volume":"26","author":"Ryan","year":"2020","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.annonc.2025.01.020","article-title":"Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors","volume":"36","author":"Riedl","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1158\/2159-8290.CD-20-1616","article-title":"Mechanisms of resistance to KRASG12C-targeted therapy","volume":"11","author":"Akhave","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1158\/2159-8290.CD-22-1420","article-title":"Co-mutations and KRAS G12C inhibitor efficacy in advanced NSCLC","volume":"13","author":"Negrao","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Chour, A., Toffart, A.-C., Berton, E., and Duruisseaux, M. (2024). Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1328728"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.ccell.2024.02.012","article-title":"Exploiting the therapeutic implications of KRAS inhibition on tumor immunity","volume":"42","author":"Downward","year":"2024","journal-title":"Cancer Cell"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/773\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:21:08Z","timestamp":1783606868000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/7\/773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,24]]},"references-count":114,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["pharmaceutics18070773"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18070773","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,24]]}}}