8C7Y

Crystal structure of BRAF V600E in complex with a hybrid compound 6

Summary for 8C7Y

• Entry DOI: 10.2210/pdb8c7y/pdb
• Descriptor: Serine/threonine-protein kinase B-raf, 1,2-ETHANEDIOL, NITRATE ION, ... (5 entities in total)
• Functional Keywords: braf, kinase, kinase inhibitor, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 66446.62

Authors

Chaikuad, A.,Bonnet, P.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2023-01-17, release date: 2023-02-22, Last modification date: 2024-06-19)

Primary citation

Arora, R.,Linders, J.T.M.,Aci-Seche, S.,Verheyen, T.,Van Heerde, E.,Brehmer, D.,Chaikuad, A.,Knapp, S.,Bonnet, P.
Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor.
Eur.J.Med.Chem., 250:115231-115231, 2023

PubMed Abstract: The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (B-Raf) kinase domain leading to heterodimerization with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization. Here we present a new B-Raf kinase domain inhibitor, based on a phenyl(1H-pyrrolo [2,3-b]pyridin-3-yl)methanone template, that represents a hybrid between 4 and 3. This novel inhibitor borrows the hinge binding region from 4 and the back pocket binding moiety from 3. We determined its binding mode, performed activity/selectivity studies, and molecular dynamics simulations in order to study the conformational effects induced by this inhibitor on wt and V600E mutant B-Raf kinase. We discovered that the inhibitor was active and selective for B-Raf, binds in a DFG-out/αC-helix-in conformation, and did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.

PubMed: 36878151
DOI: 10.1016/j.ejmech.2023.115231

Experimental method

X-RAY DIFFRACTION (1.65 Å)