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 t_1/2 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.

赖氨酸特异性去甲基化酶 1 (LSD1) 是一种 FAD 依赖性组蛋白去甲基化酶，可催化 H3K4 和 H3K9 的去甲基化，因此是治疗癌症的一个有吸引力的靶点。从高微摩尔化合物17i开始，通过生物电子等排策略描述了基于结构的新型吲哚衍生物的优化。以分子模型为基础，药物化学有效地产生了低纳摩尔 LSD1 抑制剂。其中一种化合物B35表现出优异的 LSD1 抑制作用（IC ₅₀  = 0.050 ± 0.005  μ M）和对 A549 细胞的抗增殖作用（IC ₅₀  = 0.74 ± 0.14  μ M）。进一步的 PK 研究表明化合物B35具有良好的代谢稳定性，其中 po 和 iv 的血浆t _1/2分别为 6.27 ± 0.72 h 和 8.78 ± 1.31 h。此外，抑制剂B35显示出很强的抗肿瘤作用和良好的体内安全性。同时，化合物B35调控基因与癌症中的转录错位和涉及IGFBP3的PI3K/AKT通路密切相关。总之，B35可能是一种有效的 LSD1 抑制剂，可用于进一步的药物开发。