9GH2 の概要
| エントリーDOI | 10.2210/pdb9gh2/pdb |
| 関連するPDBエントリー | 9G0Y 9G4B 9GGT 9GGU 9GGV 9GGW 9GGX 9GGY 9GGZ 9GH0 9GH1 |
| 分子名称 | GTPase KRas, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (6 entities in total) |
| 機能のキーワード | ras, gtpase, inhibitor, cell cycle |
| 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 | 21002.82 |
| 構造登録者 | |
| 主引用文献 | Parry, C.W.,Pellicano, F.,Schuttelkopf, A.W.,Beyer, K.S.,Bower, J.,Bryson, A.,Cameron, K.,Cerutti, N.M.,Clark, J.P.,Davidson, S.C.,Davies, K.,Drysdale, M.J.,Engelman, J.,Estevan-Barber, A.,Gohlke, A.,Gray, C.H.,Guthy, D.A.,Hong, M.,Hopkins, A.,Hutchinson, L.D.,Konczal, J.,Maira, M.,McArthur, D.,Mezna, M.,McKinnon, H.,Nepravishta, R.,Ostermann, N.,Pasquali, C.C.,Pollock, K.,Pugliese, A.,Rooney, N.,Schmiedeberg, N.,Shaw, P.,Velez-Vega, C.,West, C.,West, R.,Zecri, F.,Taylor, J.B. Reversible Small Molecule Multivariant Ras Inhibitors Display Tunable Affinity for the Active and Inactive Forms of Ras. J.Med.Chem., 68:9129-9161, 2025 Cited by PubMed Abstract: Activating mutations of Ras are one of the most prevalent drivers of cancer and are often associated with poor clinical outcomes. Despite FDA approval for two irreversible inhibitors that target the inactive state of KRas, significant unmet clinical need still exists, and the susceptibility of non-G12C mutants to inactive-state inhibition remains unclear. Here we report the discovery of a novel series of reversible inhibitors that bind in an enlarged version of the switch I-II pocket with nanomolar affinities. Dependent on chemotype these can either preferentially bind to the inactive or active state or bind both with similar affinity. The active-state binders inhibit the Raf interaction for wild-type Ras, and a broad range of oncogenic KRas mutants with nanomolar potency. A subseries of these molecules displays cellular inhibition of Ras-Raf binding, as well as decreased phosphorylation of the downstream protein ERK, demonstrating that potent multivariant Ras inhibitors can be accessed from this novel pocket. PubMed: 40162713DOI: 10.1021/acs.jmedchem.4c02929 主引用文献が同じPDBエントリー |
| 実験手法 | X-RAY DIFFRACTION (1.35 Å) |
構造検証レポート
検証レポート(詳細版)
をダウンロード
をダウンロード
