Molecular Design of Cyclic Peptides with Cell Membrane Permeability and Development of MDMX-p53 Inhibitor

Mai Mizuno-Kaneko; Ichihiko Hashimoto; Kenta Miyahara; Masahiro Kochi; Noriyuki Ohashi; Kyosuke Tsumura; Koo Suzuki; Takashi Tamura

doi:10.1021/acsmedchemlett.3c00102

Molecular Design of Cyclic Peptides with Cell Membrane Permeability and Development of MDMX-p53 Inhibitor

ACS Med Chem Lett. 2023 Aug 10;14(9):1174-1178. doi: 10.1021/acsmedchemlett.3c00102. eCollection 2023 Sep 14.

Authors

Mai Mizuno-Kaneko¹, Ichihiko Hashimoto², Kenta Miyahara², Masahiro Kochi², Noriyuki Ohashi², Kyosuke Tsumura², Koo Suzuki², Takashi Tamura¹

Affiliations

¹ Synthetic Organic Chemistry Laboratories, FUJIFILM Corporation, 577, Ushijima, Kaisei-machi, Ashigarakami-gun, Kanagawa 258-8577, Japan.
² Analysis Technology Center, FUJIFILM Corporation, 210, Nakanuma, Minamiashigara-shi, Kanagawa 250-0193, Japan.

PMID: 37736191
PMCID: PMC10510666 (available on 2024-09-14)
DOI: 10.1021/acsmedchemlett.3c00102

Abstract

Cyclic peptides have been expected to be one of the modalities of intracellular protein-protein interaction (PPI) inhibitors, but they are generally known to have low cell membrane permeability. In this study, we focused on the conformation of cyclic peptides in the cell membrane to determine the requirement for their cell membrane permeability through passive diffusion. Utilizing the requirement, we searched for structures with high affinity for MDMX via computational chemistry and acquired cyclic peptide 19 (P_app = 0.80 × 10^-6 cm s^-1, IC₅₀ = 0.07 μM).