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Can I read Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor on EtoBox?
Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor by Rohit Arora; Joannes T.M. Linders; Samia Aci-Sèche; Thomas Verheyen; Erika Van Heerde; Dirk Brehmer; Apirat Chaikuad; Stefan Knapp; Pascal Bonnet is a Chemistry article available to read on EtoBox.
What is Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor about?
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 ( wt 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
Who reads Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor?
It is typically read by researchers, students, and practitioners in Chemistry.
- Author
- Rohit Arora; Joannes T.M. Linders; Samia Aci-Sèche; Thomas Verheyen; Erika Van Heerde; Dirk Brehmer; Apirat Chaikuad; Stefan Knapp; Pascal Bonnet
- Publisher
- Elsevier BV
- Published
- 2023
- Language
- EN
- Field
- Chemistry (Physical Sciences)