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