1. Academic Validation
  2. Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets

  • J Am Chem Soc. 2023 Nov 8;145(44):24035-24051. doi: 10.1021/jacs.3c07145.
Atsushi Ohta 1 Mikimasa Tanada 1 Shojiro Shinohara 1 Yuya Morita 1 Kazuhiko Nakano 1 Yusuke Yamagishi 1 Ryusuke Takano 1 Shiori Kariyuki 1 Takeo Iida 1 Atsushi Matsuo 1 Kazuhisa Ozeki 1 Takashi Emura 1 Yuuji Sakurai 1 Koji Takano 1 Atsuko Higashida 1 Miki Kojima 1 Terushige Muraoka 1 Ryuuichi Takeyama 1 Tatsuya Kato 1 Kaori Kimura 1 Kotaro Ogawa 1 Kazuhiro Ohara 1 Shota Tanaka 1 Yasufumi Kikuchi 1 Nozomi Hisada 1 Ryuji Hayashi 1 Yoshikazu Nishimura 1 Kenichi Nomura 1 Tatsuhiko Tachibana 1 Machiko Irie 1 Hatsuo Kawada 1 Takuya Torizawa 1 Naoaki Murao 1 Tomoya Kotake 1 Masahiko Tanaka 1 Shiho Ishikawa 1 Taiji Miyake 1 Minoru Tamiya 1 Masako Arai 1 Aya Chiyoda 1 Sho Akai 1 Hitoshi Sase 1 Shino Kuramoto 1 Toshiya Ito 1 Takuya Shiraishi 1 Tetsuo Kojima 1 Hitoshi Iikura 1
Affiliations

Affiliation

  • 1 Research Division, Chugai Pharmaceutical Co., Ltd., 216, Totsuka-cho,Totsuka-ku, Yokohama 244-8602, Kanagawa, Japan.
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 N-alkylated cyclic peptide hits. We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156002
    99.26%, KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor
    Ras; ERK