{"doi":"10.1021/jacs.3c03886","title":"Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor","abstract":null,"journal":"Journal of the American Chemical Society","year":2023,"id":675424,"datarank":3.798962694276841,"base_score":5.099866427824199,"endowment":5.099866427824199,"self_citation_contribution":0.7649799641736299,"citation_network_contribution":3.033982730103211,"self_endowment_contribution":0.7649799641736299,"citer_contribution":3.033982730103211,"corpus_percentile":null,"corpus_rank":null,"citation_count":163,"citer_count":152,"citers_with_citation_signal":112,"citers_with_endowment":112,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1764743,"name":"Minoru Tamiya","orcid":null,"position":1,"is_corresponding":false},{"id":1764744,"name":"Atsushi Matsuo","orcid":null,"position":2,"is_corresponding":false},{"id":1764746,"name":"Aya Chiyoda","orcid":null,"position":3,"is_corresponding":false},{"id":626430,"name":"Koji Takano","orcid":"0000-0002-9200-9461","position":4,"is_corresponding":false},{"id":1764747,"name":"Toshiya Ito","orcid":"0000-0001-5402-0128","position":5,"is_corresponding":false},{"id":1764748,"name":"Machiko Irie","orcid":null,"position":6,"is_corresponding":false},{"id":1764749,"name":"Tomoya Kotake","orcid":null,"position":7,"is_corresponding":false},{"id":1764750,"name":"Ryuuichi Takeyama","orcid":null,"position":8,"is_corresponding":false},{"id":1764751,"name":"Hatsuo Kawada","orcid":null,"position":9,"is_corresponding":false},{"id":1727616,"name":"Ryuji Hayashi","orcid":null,"position":10,"is_corresponding":false},{"id":1764752,"name":"Shiho Ishikawa","orcid":null,"position":11,"is_corresponding":false},{"id":1764753,"name":"Kenichi Nomura","orcid":"0000-0003-2503-9502","position":12,"is_corresponding":false},{"id":1764754,"name":"Noriyuki Furuichi","orcid":null,"position":13,"is_corresponding":false},{"id":1764755,"name":"Yuya Morita","orcid":null,"position":14,"is_corresponding":false},{"id":1764756,"name":"Mirai Kage","orcid":null,"position":15,"is_corresponding":false},{"id":245406,"name":"Satoshi Hashimoto","orcid":"0000-0002-6445-1885","position":16,"is_corresponding":false},{"id":1764757,"name":"Keiji Nii","orcid":null,"position":17,"is_corresponding":false},{"id":1764758,"name":"Hitoshi Sase","orcid":null,"position":18,"is_corresponding":false},{"id":1764759,"name":"Kazuhiro Ohara","orcid":null,"position":19,"is_corresponding":false},{"id":1764760,"name":"Atsushi Ohta","orcid":null,"position":20,"is_corresponding":false},{"id":1764761,"name":"Shino Kuramoto","orcid":null,"position":21,"is_corresponding":false},{"id":1764762,"name":"Yoshikazu Nishimura","orcid":"0000-0003-3153-3339","position":22,"is_corresponding":false},{"id":1764763,"name":"Hitoshi Iikura","orcid":null,"position":23,"is_corresponding":false},{"id":1764764,"name":"Takuya Shiraishi","orcid":null,"position":24,"is_corresponding":false},{"id":1764742,"name":"Mikimasa Tanada","orcid":"0000-0002-5474-9274","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor","abstract":"Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including C log P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10 –6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide’s main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski’s rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.","is_dataset_classified":null,"base_score":5.087596335232384,"endowment":5.087596335232384,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"37463267","pmcid":null,"openalex_id":"https://openalex.org/W4384662540","authors":[],"funders":[],"total_grants":0,"fwci":14.6872,"citation_percentile":0.99528732,"influential_citations":0,"citation_trend":[{"year":2023,"count":7},{"year":2024,"count":53},{"year":2025,"count":61},{"year":2026,"count":40}],"oa_status":"closed","license":"https://doi.org/10.15223/policy-029","oa_locations":[{"url":"https://pubs.acs.org/doi/pdf/10.1021/jacs.3c03886","host_type":"publisher"},{"url":"https://doi.org/10.1021/jacs.3c03886","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/37463267","host_type":"repository"}],"fields_of_study":["Chemical Synthesis and Analysis","Antimicrobial Peptides and Activities","Click Chemistry and Applications","Humans","Proto-Oncogene Proteins p21(ras)","Caco-2 Cells","Peptides","Peptides, Cyclic","Molecular Conformation"],"mesh_terms":["Humans","Molecular Conformation","Peptides","Peptides, Cyclic","Proto-Oncogene Proteins p21(ras)","Caco-2 Cells"],"keywords":["Cyclic peptide","Chemistry","Peptide","Intracellular","Membrane permeability","Drug discovery","Drug","Small molecule","Bioavailability","Combinatorial chemistry","Biochemistry","Pharmacology","Membrane"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T00:31:35.299440Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}