8JJS

Human K-Ras G12D (GDP-bound) in complex with cyclic peptide inhibitor AP10343

8JJS の概要

• エントリーDOI: 10.2210/pdb8jjs/pdb
• 分子名称: Isoform 2B of GTPase KRas, MAA-ILE-SAR-SAR-7T2-SAR-IAE-LEU-MEA-MLE-7TK, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: cyclic peptide, 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: 22330.37

構造登録者

Irie, M.,Fukami, T.A.,Tanada, M.,Ohta, A.,Torizawa, T. (登録日: 2023-05-31, 公開日: 2023-07-26, 最終更新日: 2023-11-15)

主引用文献

Tanada, M.,Tamiya, M.,Matsuo, A.,Chiyoda, A.,Takano, K.,Ito, T.,Irie, M.,Kotake, T.,Takeyama, R.,Kawada, H.,Hayashi, R.,Ishikawa, S.,Nomura, K.,Furuichi, N.,Morita, Y.,Kage, M.,Hashimoto, S.,Nii, K.,Sase, H.,Ohara, K.,Ohta, A.,Kuramoto, S.,Nishimura, Y.,Iikura, H.,Shiraishi, T.
Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.
J.Am.Chem.Soc., 145:16610-16620, 2023

PubMed Abstract: Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including log can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide's main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski's rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.

PubMed: 37463267
DOI: 10.1021/jacs.3c03886

実験手法

X-RAY DIFFRACTION (1.534 Å)