Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

  • ACS Med Chem Lett. 2022 Sep 12;13(10):1568-1573. doi: 10.1021/acsmedchemlett.2c00126.
Yosuke Ota  1 ,  Yukihiro Itoh  1  2 ,  Takashi Kurohara  1  2 ,  Ritesh Singh  1  3 ,  Elghareeb E Elboray  1  4 ,  Chenliang Hu  2 ,  Farzad Zamani  2 ,  Anirban Mukherjee  2 ,  Yuri Takada  2 ,  Yasunobu Yamashita  2 ,  Mie Morita  5 ,  Mano Horinaka  5 ,  Yoshihiro Sowa  5 ,  Mitsuharu Masuda  5 ,  Toshiyuki Sakai  5 ,  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.
PMID: 36262394 DOI: 10.1021/acsmedchemlett.2c00126
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.