دورية أكاديمية
Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation
| العنوان: | Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation |
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| المؤلفون: | Beneker C.M., Rovoli M., Kontopidis G., Röring M., Galda S., Braun S., Brummer T., McInnes C. |
| المصدر: | Journal of Medicinal Chemistry ; https://www.scopus.com/inward/record.uri?eid=2-s2.0-85064746243&doi=10.1021%2facs.jmedchem.8b01288&partnerID=40&md5=5483fe0837f049cf65e0f66be88b5b94Test |
| سنة النشر: | 2019 |
| المجموعة: | University of Thessaly Institutional Repository / Ιδρυματικό Αποθετήριο Πανεπιστημίου Θεσσαλίας |
| مصطلحات موضوعية: | B Raf kinase inhibitor, B Raf kinase, mitogen activated protein kinase, mitogen activated protein kinase kinase kinase, peptide, protein binding, protein kinase inhibitor, Article, binding affinity, controlled study, dimerization, drug design, drug structure, drug synthesis, human, human cell, melanoma cell, proof of concept, signal transduction, cell line, chemistry, drug effect, MAPK signaling, metabolism, molecular dynamics, structure activity relation, synthesis, Extracellular Signal-Regulated MAP Kinases, Humans, MAP Kinase Kinase Kinases |
| الوصف: | Despite the clinical success of BRAF inhibitors like vemurafenib in treating metastatic melanoma, resistance has emerged through "paradoxical MEK/ERK signaling" where transactivation of one protomer occurs as a result of drug inhibition of the other partner in the activated dimer. The importance of the dimerization interface in the signaling potential of wild-type BRAF in cells expressing oncogenic Ras has recently been demonstrated and proposed as a site of therapeutic intervention in targeting cancers resistant to adenosine triphosphate competitive drugs. The proof of concept for a structure-guided approach targeting the dimerization interface is described through the design and synthesis of macrocyclic peptides that bind with high affinity to BRAF and that block paradoxical signaling in malignant melanoma cells occurring through this drug target. The lead compounds identified are type-IV kinase inhibitors and represent an ideal framework for conversion into next-generation BRAF inhibitors through macrocyclic drug discovery. © 2019 American Chemical Society. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 00222623 |
| العلاقة: | http://hdl.handle.net/11615/71559Test |
| DOI: | 10.1021/acs.jmedchem.8b01288 |
| الإتاحة: | https://doi.org/10.1021/acs.jmedchem.8b01288Test http://hdl.handle.net/11615/71559Test |
| رقم الانضمام: | edsbas.89E44B28 |
| قاعدة البيانات: | BASE |
| تدمد: | 00222623 |
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| DOI: | 10.1021/acs.jmedchem.8b01288 |