8S8C

Structure of Kras in complex with inhibitor MK-1084

これはPDB形式変換不可エントリーです。

8S8C の概要

• エントリーDOI: 10.2210/pdb8s8c/pdb
• 分子名称: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: nucleotide binding, gtpase, hydrolase, signal transduction, 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: 20459.38

構造登録者

Day, P.J.,Cleasby, A. (登録日: 2024-03-06, 公開日: 2024-07-10, 最終更新日: 2024-10-23)

主引用文献

Ma, X.,Sloman, D.L.,Duggal, R.,Anderson, K.D.,Ballard, J.E.,Bharathan, I.,Brynczka, C.,Gathiaka, S.,Henderson, T.J.,Lyons, T.W.,Miller, R.,Munsell, E.V.,Orth, P.,Otte, R.D.,Palani, A.,Rankic, D.A.,Robinson, M.R.,Sather, A.C.,Solban, N.,Song, X.S.,Wen, X.,Xu, Z.,Yang, Y.,Yang, R.,Day, P.J.,Stoeck, A.,Bennett, D.J.,Han, Y.
Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS G12C Inhibitor.
J.Med.Chem., 67:11024-11052, 2024

PubMed Abstract: Oncogenic mutations in the gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.

PubMed: 38924388
DOI: 10.1021/acs.jmedchem.4c00572

実験手法

X-RAY DIFFRACTION (1.9 Å)