7YUZ

Human K-Ras G12D (GDP-bound) in complex with cyclic peptide inhibitor AP8784

7YUZ の概要

• エントリーDOI: 10.2210/pdb7yuz/pdb
• 分子名称: Isoform 2B of GTPase KRas, AP8784, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: oncology, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22180.53

構造登録者

Irie, M.,Fukami, T.A.,Tanada, M.,Ohta, A.,Torizawa, T. (登録日: 2022-08-18, 公開日: 2023-07-26, 最終更新日: 2023-11-22)

主引用文献

Ohta, A.,Tanada, M.,Shinohara, S.,Morita, Y.,Nakano, K.,Yamagishi, Y.,Takano, R.,Kariyuki, S.,Iida, T.,Matsuo, A.,Ozeki, K.,Emura, T.,Sakurai, Y.,Takano, K.,Higashida, A.,Kojima, M.,Muraoka, T.,Takeyama, R.,Kato, T.,Kimura, K.,Ogawa, K.,Ohara, K.,Tanaka, S.,Kikuchi, Y.,Hisada, N.,Hayashi, R.,Nishimura, Y.,Nomura, K.,Tachibana, T.,Irie, M.,Kawada, H.,Torizawa, T.,Murao, N.,Kotake, T.,Tanaka, M.,Ishikawa, S.,Miyake, T.,Tamiya, M.,Arai, M.,Chiyoda, A.,Akai, S.,Sase, H.,Kuramoto, S.,Ito, T.,Shiraishi, T.,Kojima, T.,Iikura, H.
Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.
J.Am.Chem.Soc., 145:24035-24051, 2023

PubMed Abstract: Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol). In this study, we validated a new methodology to create oral drugs beyond the rule of 5 for intracellular tough targets by elucidating structural features and physicochemical properties for drug-like cyclic peptides and developing library technologies to afford highly -alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

PubMed: 37874670
DOI: 10.1021/jacs.3c07145

実験手法

X-RAY DIFFRACTION (1.878 Å)