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Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation.
Beneker, Chad M; Rovoli, Magdalini; Kontopidis, George; Röring, Michael; Galda, Simeon; Braun, Sandra; Brummer, Tilman; McInnes, Campbell.
Afiliación
  • Beneker CM; Drug Discovery and Biomedical Sciences , College of Pharmacy , Columbia , South Carolina 29208 , United States.
  • Rovoli M; Laboratory of Biochemistry, Department of Veterinary Medicine , University of Thessaly , Karditsa 43131 , Greece.
  • Kontopidis G; Laboratory of Biochemistry, Department of Veterinary Medicine , University of Thessaly , Karditsa 43131 , Greece.
  • Röring M; Institute of Molecular Medicine and Cell Research, Faculty of Medicine , University of Freiburg , Freiburg 79085 , Germany.
  • Galda S; Institute of Molecular Medicine and Cell Research, Faculty of Medicine , University of Freiburg , Freiburg 79085 , Germany.
  • Braun S; Institute of Molecular Medicine and Cell Research, Faculty of Medicine , University of Freiburg , Freiburg 79085 , Germany.
  • Brummer T; Institute of Molecular Medicine and Cell Research, Faculty of Medicine , University of Freiburg , Freiburg 79085 , Germany.
  • McInnes C; Centre for Biological Signalling Studies, BIOSS , University of Freiburg , Schänzlestrasse 18 , Freiburg 79104 , Germany.
J Med Chem ; 62(8): 3886-3897, 2019 04 25.
Article en En | MEDLINE | ID: mdl-30977659
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Proteínas Proto-Oncogénicas B-raf / Inhibidores de Proteínas Quinasas Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Proteínas Proto-Oncogénicas B-raf / Inhibidores de Proteínas Quinasas Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos