5VAM

BRAF in Complex with RAF709

5VAM の概要

• エントリーDOI: 10.2210/pdb5vam/pdb
• 関連するPDBエントリー: 5VAL
• 分子名称: Serine/threonine-protein kinase B-raf, N-{2-methyl-5'-(morpholin-4-yl)-6'-[(oxan-4-yl)oxy][3,3'-bipyridin]-5-yl}-3-(trifluoromethyl)benzamide (3 entities in total)
• 機能のキーワード: braf 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 : P15056
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64912.86

構造登録者

Mamo, M.,Appleton, B.A. (登録日: 2017-03-27, 公開日: 2017-06-28, 最終更新日: 2024-03-06)

主引用文献

Nishiguchi, G.A.,Rico, A.,Tanner, H.,Aversa, R.J.,Taft, B.R.,Subramanian, S.,Setti, L.,Burger, M.T.,Wan, L.,Tamez, V.,Smith, A.,Lou, Y.,Barsanti, P.A.,Appleton, B.A.,Mamo, M.,Tandeske, L.,Dix, I.,Tellew, J.E.,Huang, S.,Mathews Griner, L.A.,Cooke, V.G.,Van Abbema, A.,Merritt, H.,Ma, S.,Gampa, K.,Feng, F.,Yuan, J.,Wang, Y.,Haling, J.R.,Vaziri, S.,Hekmat-Nejad, M.,Jansen, J.M.,Polyakov, V.,Zang, R.,Sethuraman, V.,Amiri, P.,Singh, M.,Lees, E.,Shao, W.,Stuart, D.D.,Dillon, M.P.,Ramurthy, S.
Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.
J. Med. Chem., 60:4869-4881, 2017

PubMed Abstract: RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

PubMed: 28557458
DOI: 10.1021/acs.jmedchem.6b01862

実験手法

X-RAY DIFFRACTION (2.1 Å)