Identification of novel indole derivatives as highly potent and efficacious LSD1 inhibitors

• Published in: European journal of medicinal chemistry Vol. 239; p. 114523
• Main Authors: Zhang, Xiangyu, Sun, Yixiang, Huang, Hailan, Wang, Xinran, Wu, Tianxiao, Yin, Wenbo, Li, Xiaojia, Wang, Lin, Gu, Yanting, Zhao, Dongmei, Cheng, Maosheng
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.09.2022
• Subjects: A549 Cells; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis; Bioelectronic isosteric; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Epigenetic; Histone Demethylases - antagonists & inhibitors; Humans; Indole derivatives; Indoles - chemical synthesis; Indoles - pharmacology; LSD1 inhibitors; Male; Mice; Mice, Inbred BALB C; Models, Molecular; Molecular docking; Molecular Docking Simulation; Molecular Structure; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Xenograft Model Antitumor Assays; Epigenetic; Indole derivatives; LSD1 inhibitors; Bioelectronic isosteric; Molecular docking
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114523

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent histone demethylase to catalyze the demethylation of H3K4 and H3K9 and thus is an attractive target for therapeutic cancer. Starting with a high micromolar compound 17i, structure-based optimization of novel indole derivatives is described by a bioelectronic isosteric strategy. Grounded by molecular modeling, medicinal chemistry has efficiently yielded low nanomolar LSD1 inhibitors. One of the compounds, B35, exhibited excellent LSD1 inhibition (IC50 = 0.050 ± 0.005 μM) and anti-proliferation against A549 cells (IC50 = 0.74 ± 0.14 μM). The further PK studies indicated compound B35 possessed favorable metabolic stability, in which the plasma t1/2 of p.o. and i.v. were 6.27 ± 0.72 h and 8.78 ± 1.31 h, respectively. Additionally, inhibitor B35 shows a strong antitumor effect and good safety in vivo. Meanwhile, compound B35 regulated genes are closely associated with transcriptional dislocation in cancer and PI3K/AKT pathway involving IGFBP3. Taken together, B35 could be a potent LSD1 inhibitor for further drug development. [Display omitted] •Structure-based optimization of novel indole derivatives is described by a bioelectronic isosteric strategy.•The in vivo PK studies indicated compound B35 possessed favorable metabolic stability.•Compound B35 regulated genes are associated with transcriptional dislocation in PI3K/AKT pathway.