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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • 99.76%, KRAS Inhibitor, ERK Inhibitor, RAS Inhibitor
    target: Ras; ERK
    Research Areas: Cancer