Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates.

Authors :: Ota Y
Itoh Y
Kurohara T
Singh R
Elboray EE
Hu C
Zamani F
Mukherjee A
Takada Y
Yamashita Y
Morita M
Horinaka M
Sowa Y
Masuda M
Sakai T
Suzuki T
Source :: ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Sep 12; Vol. 13 (10), pp. 1568-1573. Date of Electronic Publication: 2022 Sep 12 (Print Publication: 2022).
Publication Year :: 2022
Abstract: Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1 , 9 , and 32 , conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2022 American Chemical Society.)