Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor

• Published in: Journal of the American Chemical Society Vol. 145; no. 30; pp. 16610 - 16620
• Main Authors: Tanada, Mikimasa, Tamiya, Minoru, Matsuo, Atsushi, Chiyoda, Aya, Takano, Koji, Ito, Toshiya, Irie, Machiko, Kotake, Tomoya, Takeyama, Ryuuichi, Kawada, Hatsuo, Hayashi, Ryuji, Ishikawa, Shiho, Nomura, Kenichi, Furuichi, Noriyuki, Morita, Yuya, Kage, Mirai, Hashimoto, Satoshi, Nii, Keiji, Sase, Hitoshi, Ohara, Kazuhiro, Ohta, Atsushi, Kuramoto, Shino, Nishimura, Yoshikazu, Iikura, Hitoshi, Shiraishi, Takuya
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 02.08.2023; Amer Chemical Soc
• Subjects: absorption; bioavailability; Chemistry; Chemistry, Multidisciplinary; cyclic peptides; drugs; membrane permeability; Physical Sciences; protein structure; Science & Technology; therapeutics; CHAIN; PERMEABILITY; SMALL-MOLECULE INHIBITORS; DRUG DISCOVERY; MESSENGER-RNA DISPLAY; BINDING; CYCLOSPORINE; INSIGHTS
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c03886

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10–6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide’s main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski’s rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits.