دورية أكاديمية
Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents.
العنوان: | Zurletrectinib is a next-generation TRK inhibitor with strong intracranial activity against NTRK fusion-positive tumours with on-target resistance to first-generation agents. |
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المؤلفون: | Roa P; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Foglizzo V; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Harada G; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Repetto M; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Oncology and Haemato-Oncology, University of Milan, 20133, Milan, Italy., Kulick A; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA., de Marchena M; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Auwardt S; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Sayed Ahmed S; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Bremer NV; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA., Yang SR; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Feng Y; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA.; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA., Zhou C; InnoCare Pharma Limited, Beijing, China., Kong N; InnoCare Pharma Limited, Beijing, China., Liang R; InnoCare Pharma Limited, Beijing, China., Xu H; InnoCare Pharma Limited, Beijing, China., Zhang B; InnoCare Pharma Limited, Beijing, China., Bardelli A; Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy.; IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy., Toska E; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.; Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA., Ventura A; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Drilon A; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Cocco E; Department of Biochemistry and Molecular Biology, University of Miami, Miller School of Medicine, Miami, FL, USA. exc2752@miami.edu.; Sylvester Comprehensive Cancer Center (SCCC), Miami, FL, USA. exc2752@miami.edu. |
المصدر: | British journal of cancer [Br J Cancer] 2024 Aug; Vol. 131 (3), pp. 601-610. Date of Electronic Publication: 2024 Jun 20. |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK Original Publication: London, Lewis. |
مواضيع طبية MeSH: | Protein Kinase Inhibitors*/pharmacology , Receptor, trkA*/genetics , Receptor, trkA*/antagonists & inhibitors , Drug Resistance, Neoplasm*/genetics , Drug Resistance, Neoplasm*/drug effects , Receptor, trkB*/antagonists & inhibitors , Receptor, trkB*/genetics , Xenograft Model Antitumor Assays* , Receptor, trkC*/genetics , Receptor, trkC*/antagonists & inhibitors, Humans ; Animals ; Mice ; Cell Line, Tumor ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/antagonists & inhibitors ; Rats ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Pyrazoles/pharmacology ; Glioma/drug therapy ; Glioma/genetics ; Glioma/pathology ; Pyrimidines/pharmacology ; Mutation ; Female ; Membrane Glycoproteins |
مستخلص: | Background: While NTRK fusion-positive cancers can be exquisitely sensitive to first-generation TRK inhibitors, resistance inevitably occurs, mediated in many cases by acquired NTRK mutations. Next-generation inhibitors (e.g., selitrectinib, repotrectinib) maintain activity against these TRK mutant tumors; however, there are no next-generation TRK inhibitors approved by the FDA and select trials have stopped treating patients. Thus, the identification of novel, potent and specific next-generation TRK inhibitors is a high priority. Methods: In silico modeling and in vitro kinase assays were performed on TRK wild type (WT) and TRK mutant kinases. Cell viability and clonogenic assays as well as western blots were performed on human primary and murine engineered NTRK fusion-positive TRK WT and mutant cell models. Finally, zurletrectinib was tested in vivo in human xenografts and murine orthotopic glioma models harboring TRK-resistant mutations. Results: In vitro kinase and in cell-based assays showed that zurletrectinib, while displaying similar potency against TRKA, TRKB, and TRKC WT kinases, was more active than other FDA approved or clinically tested 1 st - (larotrectinib) and next-generation (selitrectinib and repotrectinib) TRK inhibitors against most TRK inhibitor resistance mutations (13 out of 18). Similarly, zurletrectinib inhibited tumor growth in vivo in sub-cute xenograft models derived from NTRK fusion-positive cells at a dose 30 times lower when compared to selitrectinib. Computational modeling suggests this stronger activity to be the consequence of augmented binding affinity of zurletrectinib for TRK kinases. When compared to selitrectinib and repotrectinib, zurletrectinib showed increased brain penetration in rats 0.5 and 2 h following a single oral administration. Consistently, zurletrectinib significantly improved the survival of mice harboring orthotopic NTRK fusion-positive, TRK-mutant gliomas (median survival = 41.5, 66.5, and 104 days for selitrectinib, repotrectinib, and zurletrectinib respectively; P < 0.05). Conclusion: Our data identifies zurletrectinib as a novel, highly potent next-generation TRK inhibitor with stronger in vivo brain penetration and intracranial activity than other next-generation agents. (© 2024. The Author(s).) |
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معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (Protein Kinase Inhibitors) EC 2.7.10.1 (Receptor, trkA) EC 2.7.10.1 (Receptor, trkB) EC 2.7.10.1 (Receptor, trkC) 0 (Oncogene Proteins, Fusion) 0 (Pyrazoles) EC 2.7.10.1 (tropomyosin-related kinase-B, human) 0 (NTRK1 protein, human) 0 (Pyrimidines) 0 (NTRK3 protein, human) 0 (Membrane Glycoproteins) |
تواريخ الأحداث: | Date Created: 20240620 Date Completed: 20240805 Latest Revision: 20240808 |
رمز التحديث: | 20240808 |
مُعرف محوري في PubMed: | PMC11300601 |
DOI: | 10.1038/s41416-024-02760-1 |
PMID: | 38902532 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1532-1827 |
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DOI: | 10.1038/s41416-024-02760-1 |