Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation.

Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation.

Publication date: Apr 12, 2019

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.

Beneker, C.M., Rovoli, M., Kontopidis, G., R”oring, M., Galda, S., Braun, S., Brummer, T., and McInnes, C. Design and Synthesis of Type-IV Inhibitors of BRAF Kinase That Block Dimerization and Overcome Paradoxical MEK/ERK Activation. 22287. 2019 J Med Chem.

Concepts Keywords
Adenosine Triphosphate Drug discovery
Affinity Protein kinase inhibitor
BRAF Melanoma
Dimer BRAF
Dimerization Sulfonamides
Drug Discovery Vemurafenib
Drug Target Genentech
ERK Chloroarenes
Kinase Cancer treatments
Lead Compounds B-Raf inhibitor
Macrocyclic Cancer
Malignant Melanoma Clinical medicine
MEK Metastatic melanoma
Melanoma Cancers
Oncogenic
Peptides
Ras
Transactivation
Vemurafenib
Wild Type

Semantics

Type Source Name
drug DRUGBANK ATP
disease MESH cancers
drug DRUGBANK Rasagiline
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
drug DRUGBANK Spinosad
drug DRUGBANK Vemurafenib
gene UNIPROT EPHB2
gene UNIPROT MAPK1
gene UNIPROT MAP2K7
gene UNIPROT BRAF

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *