4PP7

Highly Potent and Selective 3-N-methylquinazoline-4(3H)-one Based Inhibitors of B-RafV600E Kinase

4PP7 の概要

• エントリーDOI: 10.2210/pdb4pp7/pdb
• 分子名称: Serine/threonine-protein kinase B-raf, N-{2,4-difluoro-3-[methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino]phenyl}propane-1-sulfonamide (2 entities in total)
• 機能のキーワード: serine/threonine-protein kinase b-raf, 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: 71280.16

構造登録者

Wenglowsky, S.,Ren, L.,Grina, J.,Hansen, J.D.,Laird, E.R.,Moreno, D.,Dinkel, V.,Gloor, S.L.,Hastings, G.,Rana, S.,Rasor, K.,Sturgis, H.L.,Voegtli, W.C.,Vigers, G.P.A.,Willis, B.,Mathieu, S.,Rudolph, J. (登録日: 2014-02-26, 公開日: 2014-04-09, 最終更新日: 2024-02-28)

主引用文献

Wenglowsky, S.,Ren, L.,Grina, J.,Hansen, J.D.,Laird, E.R.,Moreno, D.,Dinkel, V.,Gloor, S.L.,Hastings, G.,Rana, S.,Rasor, K.,Sturgis, H.L.,Voegtli, W.C.,Vigers, G.,Willis, B.,Mathieu, S.,Rudolph, J.
Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase.
Bioorg.Med.Chem.Lett., 24:1923-1927, 2014

PubMed Abstract: Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery.

PubMed: 24675381
DOI: 10.1016/j.bmcl.2014.03.007

実験手法

X-RAY DIFFRACTION (3.4 Å)