Article
Author: Chiyoda, Aya ; Takeyama, Ryuuichi ; Sakurai, Yuuji ; Murao, Naoaki ; Nishimura, Yoshikazu ; Arai, Masako ; Matsuo, Atsushi ; Takano, Ryusuke ; Akai, Sho ; Torizawa, Takuya ; Tanaka, Masahiko ; Emura, Takashi ; Ohara, Kazuhiro ; Kotake, Tomoya ; Ozeki, Kazuhisa ; Morita, Yuya ; Ito, Toshiya ; Kojima, Tetsuo ; Hayashi, Ryuji ; Tanaka, Shota ; Muraoka, Terushige ; Sase, Hitoshi ; Tachibana, Tatsuhiko ; Kimura, Kaori ; Ogawa, Kotaro ; Tamiya, Minoru ; Kawada, Hatsuo ; Kikuchi, Yasufumi ; Shinohara, Shojiro ; Hisada, Nozomi ; Kato, Tatsuya ; Higashida, Atsuko ; Kariyuki, Shiori ; Iida, Takeo ; Takano, Koji ; Ohta, Atsushi ; Irie, Machiko ; Tanada, Mikimasa ; Miyake, Taiji ; Iikura, Hitoshi ; Nomura, Kenichi ; Kojima, Miki ; Ishikawa, Shiho ; Shiraishi, Takuya ; Yamagishi, Yusuke ; Kuramoto, Shino ; Nakano, Kazuhiko
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 N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.