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In this study, TrkB expression in available cell lines was characterized, and allosteric inhibitors of ligand-activated TrkB were designed, characterized, and tested. The designed compounds commonly bear a triazole group at their center, which bridges three aromatic components. Based on the chemical design, 25 compounds were synthesized for the cell-based assay to examine the neuroblastoma cell growth inhibition. Several cell lines were used in the assay based on TrkB expression levels. TrkB non-enhanced and TrkA overexpressing cell cultures were also tested for comparison. Many of the synthesized compounds suppressed the phosphorylation of the TrkB (cytoplasmic side) induced by brain-derived neurotrophic factor (BDNF) binding to the extracellular domain of TrkB. Several compounds showed effective suppression of phosphorylation to a similar degree as larotrectinib, an approved TrkB inhibitor targeting the cytoplasmic tyrosine kinase domain. The compounds\u2019 potency to suppress neuroblastoma cell growth was evaluated using a basal high TrkB-expressing culture. Select compounds showed strong cell growth suppression, with 50% inhibitory activities below 30 nM. Two potent compounds were also tested to determine their inhibitory activities on other cell lines. Cell growth inhibition was observed for three cell cultures, but moderate for one. Neither the approved TrkB inhibitor, larotrectinib, nor our allosteric compounds could completely inhibit the growth of all neuroblastoma cell lines natively expressing TrkB.<\/jats:p>","DOI":"10.1021\/acschembio.6c00423","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:02:26Z","timestamp":1786611746000},"page":"2263-2274","source":"Crossref","is-referenced-by-count":0,"title":["Allosteric Inhibition of TrkB Activation as Related to Neuroblastoma by Triazole Bridged Compounds"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6103-4448","authenticated-orcid":true,"given":"Samuel V.","family":"Rasmussen","sequence":"first","affiliation":[{"name":"Children\u2019s Cancer Therapy Development Institute , , ,","place":["Hillsboro, Oregon, United States, 97006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shefali","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Therapy Development Institute , , ,","place":["Hillsboro, Oregon, United States, 97006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Lashyro","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Therapy Development Institute , , ,","place":["Hillsboro, Oregon, United States, 97006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Lian","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Therapy Development Institute , , ,","place":["Hillsboro, Oregon, United States, 97006"]},{"name":"The First Affiliated Hospital of Zhengzhou University , , , ,","place":["Zhengzhou, Henan, China, 450052"]},{"name":"The First Affiliated Hospital of Zhengzhou University , , , ,","place":["Zhengzhou, Henan, China, 450052"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Maris","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia , , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]},{"name":"Perelman School of Medicine at the University of Pennsylvania , , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvin","family":"Farrel","sequence":"additional","affiliation":[{"name":"Children's Hospital of Philadelphia , , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]},{"name":"Perelman School of Medicine at the University of Pennsylvania , , , ,","place":["Philadelphia, Pennsylvania, United States, 19104"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6728-6857","authenticated-orcid":true,"given":"Robert C.","family":"Doebele","sequence":"additional","affiliation":[{"name":"University of Colorado Cancer Center , , ,","place":["Aurora, Colorado, United States, 80045"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4705-4412","authenticated-orcid":true,"given":"Tyuji","family":"Hoshino","sequence":"additional","affiliation":[{"name":"Chiba University , , ,","place":["Chiba, Japan, 260-8675"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Keller","sequence":"additional","affiliation":[{"name":"Children\u2019s Cancer Therapy Development Institute , , ,","place":["Hillsboro, Oregon, United States, 97006"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"2026101511071449800_cit1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.927218","article-title":"Comparison of Incidence and Outcomes of Neuroblastoma in Children, Adolescents, and Adults in the United States: A Surveillance, Epidemiology, and End Results (SEER) Program Population Study","volume":"26","author":"Yan","year":"2020","journal-title":"Med. 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Blood Cancer."},{"key":"2026101511071449800_cit5","first-page":"3737","article-title":"Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity","volume":"56","author":"Scala","year":"1996","journal-title":"Cancer Res."},{"key":"2026101511071449800_cit6","doi-asserted-by":"publisher","first-page":"3244","DOI":"10.1158\/1078-0432.CCR-08-1815","article-title":"Trk receptor expression and inhibition in neuroblastomas","volume":"15","author":"Brodeur","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"2026101511071449800_cit7","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.847572","article-title":"TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions","volume":"16","author":"Tessarollo","year":"2022","journal-title":"Front. 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