{"doi":"10.1038/srep43908","title":"Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity","abstract":"<jats:title>Abstract</jats:title><jats:p>TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC<jats:sub>50s</jats:sub> in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.</jats:p>","journal":"Scientific Reports","year":2017,"id":628205,"datarank":0.5983476069846413,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.0,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"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":798423,"name":"Sushil Kumar","orcid":"0000-0001-6680-718X","position":1,"is_corresponding":false},{"id":1626372,"name":"Nitu Bansal","orcid":null,"position":2,"is_corresponding":false},{"id":231042,"name":"Kamalendra Singh","orcid":"0000-0002-3031-5260","position":3,"is_corresponding":false},{"id":421796,"name":"Vladyslav Kholodovych","orcid":"0000-0002-2203-387X","position":4,"is_corresponding":false},{"id":1626373,"name":"Thomas Comollo","orcid":null,"position":5,"is_corresponding":false},{"id":424907,"name":"Youyi Peng","orcid":"0000-0003-4797-995X","position":6,"is_corresponding":false},{"id":245459,"name":"Sergei V. 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Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC<jats:sub>50s</jats:sub> in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.</jats:p>","is_dataset_classified":null,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"28272423","pmcid":"PMC5341070","openalex_id":"https://openalex.org/W2594344231","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P30 CA072720","title":null},{"funder_name":"National Institutes of Health","grant_id":"3R01CA165077-06S1","title":"Non-canonical signal pathway for Crk in breast cancer"},{"funder_name":"National Institutes of Health","grant_id":"3P30CA072720-07S2","title":"CANCER CENTER SUPPORT GRANT"}],"total_grants":3,"fwci":2.1937,"citation_percentile":0.87827007,"influential_citations":0,"citation_trend":[{"year":2017,"count":3},{"year":2018,"count":5},{"year":2019,"count":4},{"year":2020,"count":10},{"year":2021,"count":2},{"year":2022,"count":4},{"year":2023,"count":6},{"year":2024,"count":7},{"year":2025,"count":10},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.nature.com/articles/srep43908.pdf","host_type":"journal"},{"url":"https://www.nature.com/articles/srep43908.pdf","host_type":"publisher"},{"url":"https://www.nature.com/articles/srep43908","host_type":"publisher"},{"url":"https://doi.org/10.1038/srep43908","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/28272423","host_type":"repository"},{"url":"https://scholarship.libraries.rutgers.edu/esploro/outputs/journalArticle/Small-molecule-inhibitors-block-Gas6-inducible-TAM/991031665280104646","host_type":"journal"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5341070","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC5341070","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC5341070?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1038/srep43908","host_type":""},{"url":"https://dx.doi.org/10.1038/srep43908","host_type":""}],"fields_of_study":["Phagocytosis and Immune Regulation","Pancreatic function and diabetes","Complement system in diseases","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["c-Mer Tyrosine Kinase","Axl Receptor Tyrosine Kinase","Growth Arrest-Specific Protein 6","Animals","Binding Sites","Body Weight","Humans","Isoxazoles","Neoplasms","Piperazines","Proto-Oncogene Proteins","Transplantation, Heterologous","Mice, SCID","Mice, Inbred NOD","Receptor Protein-Tyrosine Kinases","Intercellular Signaling Peptides and Proteins","Cell Line, Tumor","Protein Kinase Inhibitors","Mice","Carcinogenesis"],"keywords":["GAS6","MERTK","Ectodomain","Receptor tyrosine kinase","Cancer research","AXL receptor tyrosine kinase","Biology","Tyrosine kinase","Chemistry","Receptor","Kinase","Cell biology","Signal transduction","Biochemistry","Binding Sites","c-Mer Tyrosine Kinase","Growth Arrest-Specific Protein 6","Carcinogenesis","Body Weight","Transplantation, Heterologous","Receptor Protein-Tyrosine Kinases","Isoxazoles","Mice, SCID","Article","Piperazines","Mice","Mice, Inbred NOD","Cell Line, Tumor","Neoplasms","Proto-Oncogene Proteins","Animals","Humans","Intercellular Signaling Peptides and Proteins","Protein Kinase Inhibitors"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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