6OIM

Crystal Structure of human KRAS G12C covalently bound to AMG 510

6OIM の概要

• エントリーDOI: 10.2210/pdb6oim/pdb
• 分子名称: GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: inhibitor, gtpase, signaling protein
• 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: 22068.73

構造登録者

Mohr, C. (登録日: 2019-04-09, 公開日: 2019-11-06, 最終更新日: 2024-11-13)

主引用文献

Canon, J.,Rex, K.,Saiki, A.Y.,Mohr, C.,Cooke, K.,Bagal, D.,Gaida, K.,Holt, T.,Knutson, C.G.,Koppada, N.,Lanman, B.A.,Werner, J.,Rapaport, A.S.,San Miguel, T.,Ortiz, R.,Osgood, T.,Sun, J.R.,Zhu, X.,McCarter, J.D.,Volak, L.P.,Houk, B.E.,Fakih, M.G.,O'Neil, B.H.,Price, T.J.,Falchook, G.S.,Desai, J.,Kuo, J.,Govindan, R.,Hong, D.S.,Ouyang, W.,Henary, H.,Arvedson, T.,Cee, V.J.,Lipford, J.R.
The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.
Nature, 575:217-223, 2019

PubMed Abstract: KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

PubMed: 31666701
DOI: 10.1038/s41586-019-1694-1

実験手法

X-RAY DIFFRACTION (1.65 Å)