7P3V

B-Raf V600E structure bound to a new inhibitor

7P3V の概要

• エントリーDOI: 10.2210/pdb7p3v/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, ~{N}-[3-[5-(2-azanylpyrimidin-4-yl)-2-[(3~{S})-morpholin-3-yl]-1,3-thiazol-4-yl]-2-fluoranyl-phenyl]-2,5-bis(fluoranyl)benzenesulfonamide (3 entities in total)
• 機能のキーワード: inhibitor complex, drug design, domain swapping, oncoprotein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63937.20

構造登録者

Schneider, M.,Gelin, M.,Cohen-Gonsaud, M.,Labesse, G. (登録日: 2021-07-08, 公開日: 2021-11-03, 最終更新日: 2024-01-31)

主引用文献

Schneider, M.,Delfosse, V.,Gelin, M.,Grimaldi, M.,Granell, M.,Heriaud, L.,Pons, J.L.,Cohen Gonsaud, M.,Balaguer, P.,Bourguet, W.,Labesse, G.
Structure-Based and Knowledge-Informed Design of B-Raf Inhibitors Devoid of Deleterious PXR Binding.
J.Med.Chem., 65:1552-1566, 2022

PubMed Abstract: Dabrafenib is an anticancer drug currently used in the clinics, alone or in combination. However, dabrafenib was recently shown to potently activate the human nuclear receptor pregnane X receptor (PXR). PXR activation increases the clearance of various chemicals and drugs, including dabrafenib itself. It may also enhance cell proliferation and tumor aggressiveness. Therefore, there is a need for rational design of a potent protein kinase B-Raf inhibitor devoid of binding to the secondary target PXR and resisting rapid metabolism. By determining the crystal structure of dabrafenib bound to PXR and analyzing its mode of binding to both PXR and its primary target, B-Raf-V600E, we were able to derive new compounds with nanomolar activity against B-Raf and no detectable affinity for PXR. The crystal structure of B-Raf in complex with our lead compound revealed a subdomain swapping of the activation loop with potentially important functional implications for a prolonged inhibition of B-Raf-V600E.

PubMed: 34958586
DOI: 10.1021/acs.jmedchem.1c01354

実験手法

X-RAY DIFFRACTION (2.37 Å)