7RT2

Crystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound

7RT2 の概要

• エントリーDOI: 10.2210/pdb7rt2/pdb
• 関連するPDBエントリー: 7RPZ
• 分子名称: Isoform 2B of GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: oncoprotein, g12d, gtpase, kras, oncology, kras4b, mrtx-1133, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20545.02

構造登録者

Gunn, R.J.,Thomas, N.C.,Xiaolun, W.,Lawson, J.D.,Marx, M.A. (登録日: 2021-08-12, 公開日: 2021-12-22, 最終更新日: 2024-03-06)

主引用文献

Wang, X.,Allen, S.,Blake, J.F.,Bowcut, V.,Briere, D.M.,Calinisan, A.,Dahlke, J.R.,Fell, J.B.,Fischer, J.P.,Gunn, R.J.,Hallin, J.,Laguer, J.,Lawson, J.D.,Medwid, J.,Newhouse, B.,Nguyen, P.,O'Leary, J.M.,Olson, P.,Pajk, S.,Rahbaek, L.,Rodriguez, M.,Smith, C.R.,Tang, T.P.,Thomas, N.C.,Vanderpool, D.,Vigers, G.P.,Christensen, J.G.,Marx, M.A.
Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS G12D Inhibitor.
J.Med.Chem., 65:3123-3133, 2022

PubMed Abstract: KRAS, the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS, selective inhibition of KRAS presents a significant challenge due to the requirement of inhibitors to bind KRAS with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS mutant xenograft mouse tumor model.

PubMed: 34889605
DOI: 10.1021/acs.jmedchem.1c01688

実験手法

X-RAY DIFFRACTION (1.59 Å)