Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent anti-proliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP2509 with IC50 values ranging from 0.23 to 1.56 mu M. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

LSD1 and HDAC are closely related in various human cancers, and simultaneous pharmacological inhibition of them can have synergistic anti-cancer effects. Novel LSD1/HDAC bifunctional inhibitors were designed and synthesized, with compounds 5d and 5m showing potent anti-cancer activities and selectivity against other enzymes. Compound 5m, in particular, demonstrated superior in vitro anticancer potency against gastric cancer cell lines compared to existing drugs.