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<p>Lysine-specific demethylase-1 (LSD1) is an epigenetic enzyme overexpressed in several cancers, including acute myeloid leukemia (AML), estrogen receptor (ER)-negative breast cancer, and non-small cell lung cancer (NSCLC). As a critical therapeutic target, LSD1 has attracted considerable attention in drug discovery. Previously, a series of amino-carboxamide benzothiazole derivatives were designed and synthesized, leading to the identification of a hit compound ((S)-N-(benzo[d]thiazol-2-yl)-3-(((1-benzylpyrrolidin-3-yl)amino)methyl)benzamide, <b>1</b>) with an IC₅₀ value of 18.4&#xa0;µM. A first round of optimization yielded two derivatives with IC₅₀ values below 5&#xa0;µM, indicating notable improvements in inhibitory potency. Building on these findings, a second optimization phase focused on isosteric replacement of the benzothiazole core to further enhance activity. In this study, sixteen novel analogs were synthesized and evaluated in vitro against LSD1. Compounds <b>18</b>, <b>23</b>, and <b>26</b> exhibited improved inhibitory activity compared to compound <b>1</b>, providing valuable insights into the structure–activity relationships (SAR) of this series and guiding future development of potent LSD1 inhibitors with potential anticancer applications.</p> Graphical abstract <p></p>

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Hit-to-lead optimization of heteroaryl amino-carboxamides as LSD1 inhibitors: part II

  • 期刊论文

  • 发表日期：

    2026年5月25日

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  • Dalia Ammar,
  • Soraya Alnabulsi,
  • Rufaida Al Zoubi

摘要

Lysine-specific demethylase-1 (LSD1) is an epigenetic enzyme overexpressed in several cancers, including acute myeloid leukemia (AML), estrogen receptor (ER)-negative breast cancer, and non-small cell lung cancer (NSCLC). As a critical therapeutic target, LSD1 has attracted considerable attention in drug discovery. Previously, a series of amino-carboxamide benzothiazole derivatives were designed and synthesized, leading to the identification of a hit compound ((S)-N-(benzo[d]thiazol-2-yl)-3-(((1-benzylpyrrolidin-3-yl)amino)methyl)benzamide, 1) with an IC₅₀ value of 18.4 µM. A first round of optimization yielded two derivatives with IC₅₀ values below 5 µM, indicating notable improvements in inhibitory potency. Building on these findings, a second optimization phase focused on isosteric replacement of the benzothiazole core to further enhance activity. In this study, sixteen novel analogs were synthesized and evaluated in vitro against LSD1. Compounds 18, 23, and 26 exhibited improved inhibitory activity compared to compound 1, providing valuable insights into the structure–activity relationships (SAR) of this series and guiding future development of potent LSD1 inhibitors with potential anticancer applications.

Graphical abstract