4EHE

B-Raf Kinase Domain in Complex with an Aminothienopyrimidine-based Inhibitor

4EHE の概要

• エントリーDOI: 10.2210/pdb4ehe/pdb
• 関連するPDBエントリー: 4EHG
• 分子名称: Serine/threonine-protein kinase B-raf, 4-amino-N-{2,6-difluoro-3-[(propylsulfonyl)amino]phenyl}thieno[3,2-d]pyrimidine-7-carboxamide (2 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus (By similarity): P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71290.16

構造登録者

Voegtli, W.C. (登録日: 2012-04-02, 公開日: 2013-04-24, 最終更新日: 2024-02-28)

主引用文献

Mathieu, S.,Gradl, S.N.,Ren, L.,Wen, Z.,Aliagas, I.,Gunzner-Toste, J.,Lee, W.,Pulk, R.,Zhao, G.,Alicke, B.,Boggs, J.W.,Buckmelter, A.J.,Choo, E.F.,Dinkel, V.,Gloor, S.L.,Gould, S.E.,Hansen, J.D.,Hastings, G.,Hatzivassiliou, G.,Laird, E.R.,Moreno, D.,Ran, Y.,Voegtli, W.C.,Wenglowsky, S.,Grina, J.,Rudolph, J.
Potent and selective aminopyrimidine-based B-raf inhibitors with favorable physicochemical and pharmacokinetic properties.
J.Med.Chem., 55:2869-2881, 2012

PubMed Abstract: Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-Raf(V600E) mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-Raf(V600E) mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.

PubMed: 22335519
DOI: 10.1021/jm300016v

実験手法

X-RAY DIFFRACTION (3.3 Å)