Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

Yosuke Ota; Yukihiro Itoh; Takashi Kurohara; Ritesh Singh; Elghareeb E Elboray; Chenliang Hu; Farzad Zamani; Anirban Mukherjee; Yuri Takada; Yasunobu Yamashita; Mie Morita; Mano Horinaka; Yoshihiro Sowa; Mitsuharu Masuda; Toshiyuki Sakai; Takayoshi Suzuki

doi:10.1021/acsmedchemlett.2c00126

Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

ACS Med Chem Lett. 2022 Sep 12;13(10):1568-1573. doi: 10.1021/acsmedchemlett.2c00126. eCollection 2022 Oct 13.

Authors

Yosuke Ota¹, Yukihiro Itoh^{1

2}, Takashi Kurohara^{1

2}, Ritesh Singh^{1

3}, Elghareeb E Elboray^{1

4}, Chenliang Hu², Farzad Zamani², Anirban Mukherjee², Yuri Takada², Yasunobu Yamashita², Mie Morita⁵, Mano Horinaka⁵, Yoshihiro Sowa⁵, Mitsuharu Masuda⁵, Toshiyuki Sakai⁵, Takayoshi Suzuki^{1

2

6}

Affiliations

¹ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 606-0823, Japan.
² SANKEN, Osaka University, Ibaraki, Osaka 567-0047, Japan.
³ Department of Chemistry, Central University of Rajasthan, Ajmer 305817, India.
⁴ Department, Faculty of Science, South Valley University, Qena 83523, Egypt.
⁵ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
⁶ CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.

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.