Discovery Of New Natural Product-based LSD1 Inhibitors And Their Anti-tumor Evaluation

ObjectiveTo reveal the anti-leukemia activity and mechanisms of the benzyltetrahydroisoquinoline alkaloid higenamine and its structural analogs;To reveal the anti-lung cancer activity and mechanisms of the new chalcone-based compounds;To discover natural product-like LSD1 inhibitors with novel structures,well-characterized mechanisms and good drug-like properties.MethodsThrough the screening of the natural product library,it was found that the hit compound higenamine could target LSD1;To reveal its possible mode of action through molecular docking simulation,and evaluate its anti-leukemia activity and mechanism at the molecular and cellular levels;To conduct structure-based drug design and structure-activity relationship studies based on the docking model of higenamine;To investigate the anti-leukemia activity and mechanism of lead compounds at the molecular,cellular and animal levels,and evaluate the pharmacokinetic properties through the liver microsomal metabolic stability and pharmacokinetic studies.In view of the inhibitory activity of natural flavonoids on LSD1,a series of new chalcone LSD1 inhibitors were designed and synthesized by using ring-opening and scaffold hopping strategies,and the possible modes of action were revealed through the molecular docking,and the anti-lung cancer activity and related mechanisms were explored at the molecular and cellular levels.To evaluate its pharmacokinetic properties using liver microsomal metabolic stability and pharmacokinetic studies.ResultsThe anti-leukemic activity and mechanisms of higenamine were reported for the first time,and the non-traditional pharmacological mechanism of its anti-leukemia activity through epigenetic regulation was revealed;two series of higenamine analogs were designed and synthesized,among which compound FY-56 had good inhibitory activity on LSD1 with an IC50 value of 42 nM.It had a certain therapeutic effect on leukemia in both in vitro and in vivo models.FY-56 had good liver microsomal metabolic stability and good pharmacokinetic properties.New chalcone-based compounds were obtained through ring-opening and scaffold hopping strategies.Among them,compound 8a-s were able to inhibit the demethylase of LSD1,and the lead compound FY-148 inactivated LSD1 effectively with an IC50 value of 150 nM;In the in vitro model,FY-148 showed good growth inhibition of lung cancer cells;the liver microsomal metabolic stability and pharmacokinetics studies indicated that FY-148 were metabolically unstable,had a high clearance rate,short half-life and low oral bioavailability.ConclusionHigenamine and its analogues exerted the anti-leukemia activity by inhibiting LSD1.The lead compound FY-56 had good liver microsomal metabolic stability,low clearance rate and good pharmacokinetic properties.The new chalcone-based compounds can also exert anti-lung cancer activity by inhibiting LSD1,but the lead compound FY-148 had poor pharmacokinetic properties.We reported three series of new LSD1 inhibitors with a total of 5 types of frameworks.We have discovered natural product-like LSD1 inhibitors with novel structures,well-characterized mechanisms and good drug-like properties.