Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets
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...
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| Veröffentlicht in: | Journal of the American Chemical Society 2023-11, Vol.145 (44), p.24035-24051 |
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| creator | Ohta, Atsushi Tanada, Mikimasa Shinohara, Shojiro Morita, Yuya Nakano, Kazuhiko Yamagishi, Yusuke Takano, Ryusuke Kariyuki, Shiori Iida, Takeo Matsuo, Atsushi Ozeki, Kazuhisa Emura, Takashi Sakurai, Yuuji Takano, Koji Higashida, Atsuko Kojima, Miki Muraoka, Terushige Takeyama, Ryuuichi Kato, Tatsuya Kimura, Kaori Ogawa, Kotaro Ohara, Kazuhiro Tanaka, Shota Kikuchi, Yasufumi Hisada, Nozomi Hayashi, Ryuji Nishimura, Yoshikazu Nomura, Kenichi Tachibana, Tatsuhiko Irie, Machiko Kawada, Hatsuo Torizawa, Takuya Murao, Naoaki Kotake, Tomoya Tanaka, Masahiko Ishikawa, Shiho Miyake, Taiji Tamiya, Minoru Arai, Masako Chiyoda, Aya Akai, Sho Sase, Hitoshi Kuramoto, Shino Ito, Toshiya Shiraishi, Takuya Kojima, Tetsuo Iikura, Hitoshi |
| description | 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. |
| doi_str_mv | 10.1021/jacs.3c07145 |
| format | Article |
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We discovered a KRAS inhibitory clinical compound (LUNA18) as the first example of our platform technology.</description><subject>antibodies</subject><subject>cyclic peptides</subject><subject>intracellular space</subject><subject>methodology</subject><subject>molecular weight</subject><issn>0002-7863</issn><issn>1520-5126</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNqFkM1Lw0AQxRdRsFZv_gF79GDqfiXZHqV-FaoFqV7DJJmkKdts3d0g_e9NaMGL4GmY4fce8x4h15xNOBP8bgOFn8iCpVzFJ2TEY8GimIvklIwYYyJKdSLPyYX3m35VQvMRaT7BNCWExrbUVhToG37TVwxrW1pj6z0Nls4cQkC6dGDog-tqT3Pc27akYY30vTM4KGNaWUfnbXBQoDGdAUdXtqvXdAWuxuAvyVkFxuPVcY7Jx9PjavYSLZbP89n9IgLFWIjKXILgWiolipLFVan6GLpEASrVupgqqLTWuVCQIGCeVIVmOYppoaZprJJEjsnNwXfn7FeHPmTbxg8vQYu285lkiqk0lrH8FxVa85RzPuU9entAC2e9d1hlO9dswe0zzrKh_GwoPzuW_-s8HDe2c20f-W_0BzdghC8</recordid><startdate>20231108</startdate><enddate>20231108</enddate><creator>Ohta, 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| source | ACS Publications |
| subjects | antibodies cyclic peptides intracellular space methodology molecular weight |
| title | Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets |
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