4R5Y

The complex structure of Braf V600E kinase domain with a novel Braf inhibitor

4R5Y の概要

• エントリーDOI: 10.2210/pdb4r5y/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, 5-({(1R,1aS,6bR)-1-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl}oxy)-3,4-dihydro-1,8-naphthyridin-2(1H)-one (2 entities in total)
• 機能のキーワード: kinase, signal transduction, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67607.11

構造登録者

Feng, Y.,Peng, H.,Zhang, Y.,Liu, Y.,Wei, M. (登録日: 2014-08-22, 公開日: 2016-02-24, 最終更新日: 2024-02-28)

主引用文献

Tang, Z.,Yuan, X.,Du, R.,Cheung, S.H.,Zhang, G.,Wei, J.,Zhao, Y.,Feng, Y.,Peng, H.,Zhang, Y.,Du, Y.,Hu, X.,Gong, W.,Liu, Y.,Gao, Y.,Liu, Y.,Hao, R.,Li, S.,Wang, S.,Ji, J.,Zhang, L.,Li, S.,Sutton, D.,Wei, M.,Zhou, C.,Wang, L.,Luo, L.
BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers.
Mol.Cancer Ther., 14:2187-2197, 2015

PubMed Abstract: Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF(V600E) metastatic melanoma, their clinical efficacy in BRAF(V600E) colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAF(V600E)-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF(V600E) and EGFR mutation/amplification. In BRAF(V600E) colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAF(V600E) mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF(V600E) mutation.

PubMed: 26208524
DOI: 10.1158/1535-7163.MCT-15-0262

実験手法

X-RAY DIFFRACTION (3.5 Å)