Targeting Cancer with PCPA‐Drug Conjugates: LSD1 Inhibition‐Triggered Release of 4‐Hydroxytamoxifen

Abstract

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.

Drug Design Concepts for LSD1‐Selective Inhibitors

“…Recently, targeting LSD1‐containing complexes by one molecule, such as pan‐KDM inhibitors, and dual LSD1‐HDAC inhibitors has been shown to be effective for targeting cancers and other diseases, because they are expected to show synergistic or additive pharmacological activities. In addition, the strategy of using PDCs ( 21 ) to target cancers overexpressing LSD1 can be applied to other drugs such as cytotoxic drugs and other epigenetic drugs targeting nuclear complexes including LSD1 …”

“…Therefore, TGS could be a powerful strategy for drug discovery. Using TGS strategies, we have identified several epigenetic modulators including HDAC inhibitors,, SIRT inhibitors, and LSD1 inhibitors . In this section, we highlight the discovery of LSD1‐selective inhibitors using TGS strategies based on our original ideas.…”

“…In 2016, a new prodrug strategy for targeting cancer cells where LSD1 is overexpressed, was proposed, in which PCPA‐drug conjugates (PDCs, 21 ) were designed based on the LSD1 inhibition by PCPA ( 1 ), (Figure a). PDCs would release a drug selectively in the cancer cells where LSD1 is overexpressed, and would not release a drug in the normal cells where LSD1 is hardly expressed (Figure a), indicating their potential as prodrugs that selectively release a drug in cancer cells.…”

“…As prototypes of PDCs, PCPA‐tamoxifen conjugates ( 21a and 21b ) were designed and synthesized (Figure b) . PCPA‐tamoxifen conjugates ( 21a and 21b ) inhibited LSD1 irreversibly, but did MAOs weakly (Figure b).…”

Design, Synthesis, and Biological Evaluation of a Conjugate of 5-Fluorouracil and an LSD1 Inhibitor

“…Small molecule-based prodrugs have also proven useful for achieving enhanced efficacies and reduced side effects of anticancer drugs and represent an effective method to avoid the aforementioned problems. 3) Thus, the development of a novel prodrug strategy using small molecules may yield improvements in targeted cancer therapies.…”