Design, synthesis, and biological evaluation of phenylcyclopropylamine-entinostat conjugates that selectively target cancer cells

Bioorg Med Chem. 2024 Feb 15:100:117632. doi: 10.1016/j.bmc.2024.117632.

Yosuke Ota ¹, Yukihiro Itoh ², Yuri Takada ³, Yasunobu Yamashita ³, Chenliang Hu ³, Mano Horinaka ¹, Yoshihiro Sowa ¹, Mitsuharu Masuda ¹, Toshiyuki Sakai ¹, Takayoshi Suzuki ⁴

Affiliations

1 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan.
2 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan; SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
3 SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
4 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamo-hangi-cho, Sakyo-ku, Kyoto 603-0823, Japan; SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan. Electronic address: tkyssuzuki@sanken.osaka-u.ac.jp.

PMID: 38340642 DOI: 10.1016/j.bmc.2024.117632

Abstract

Small molecule-based selective Cancer cell-targeting can be a desirable Anticancer therapeutic strategy. Aiming to discover such small molecules, we previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) that selectively release Anticancer agents in Cancer cells where lysine-specific demethylase 1 (LSD1) is overexpressed. In this work, we designed PCPA-entinostat conjugates for selective Cancer cell targeting. PCPA-entinostat conjugate 12 with a 4-oxybenzyl group linker released entinostat in the presence of LSD1 in in vitro assays and selectively inhibited the growth of Cancer cells in preference to normal cells, suggesting the potential of PCPA-entinostat conjugates as novel Anticancer drug delivery small molecules.

Keywords

Anticancer agent; Entinostat; LSD1; Prodrug; Targeted therapy.

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