2. Academic Validation
  3. Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates

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

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.

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