Design, synthesis and biological evaluation of novel benzofuran derivatives as potent LSD1 inhibitors

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as promising target for therapeutic cancer. Herein, series of benzofuran derivatives were designed, synthesized and biochemical evaluated novel LSD1 inhibitors based on scaffold hopping conformational restriction strategy. Most the compounds potently suppressed enzymatic activities inhibited tumor cells proliferation. In particular, representative compound 17i exhibited excellent inhibition at molecular levels with IC50 = 0.065 ?M, well anti-proliferation against MCF-7, MGC-803, H460, A549 THP-1 values 2.90 ± 0.32, 5.85 0.35, 2.06 0.27, 5.74 1.03 6.15 0.49 respectively. The binding modes these rationalized by docking. Meanwhile, preliminary druggability evaluation showed that displayed favorable liver microsomal stability weak inhibitory activity CYPs 10 ?M. Remarkably, H460 xenograft tumors studies revealed demonstrated robust in vivo antitumor efficacy without significant side effects. All results could represent lead further development.