Discovery of new tranylcypromine derivatives as highly potent LSD1 inhibitors.

Tranylcypromine (TCP)-based structural modifications lead to the discovery of new LSD1 inhibitors, of which compounds 26b and 29b effectively inhibit LSD1 with the IC50 values of 17 and 11 nM, respectively and also show good selectivity over MAO-B. Mechanistic studies showed that compound 29b concentration-dependently induced H3K4me1/2 accumulation in LSD1 overexpressed MGC-803 cells and also inhibited metastasis of MGC-803 cells. Collectively, both compounds could be promising lead compounds for further investigation.

Targeting histone demethylase KDM5B for cancer treatment.

KDM5B (Lysine-Specific Demethylase 5B) erases the methyl group from H3K4me2/3, which performs wide regulatory effects on chromatin structure, and represses the transcriptional function of genes. KDM5B functions as an oncogene and associates with human cancers closely. Targeting KDM5B has been a promising direction for curing cancer since the emergence of potent KDM5B inhibitor CPI-455. In this area, most reported KDM5B inhibitors are Fe (Ⅱ) chelators, which also compete with the cofactor 2-OG in the active pockets. Besides, Some KDM5B inhibitors have been identified through high throughput screening or biochemical screening. In this reviewing article, we summarized the pioneering progress in KDM5B to provide a comprehensive realization, including crystal structure, transcriptional regulation function, cancer-related functions, development of inhibitors, and SAR studies. We hope to provide a comprehensive overview of KDM5B and the development of KDM5B inhibitors.

Potent hydrazone derivatives targeting esophageal cancer cells.

Hydrazone and their derivatives are a series of highly active molecules, which are widely used as lead compounds for the research and development of new anti-cancer drugs. In this study, 20 compounds were synthesized, based on this scaffold and their in vitro cytotoxicity against 6 cancer cell lines, including EC9706, SMMC-7721, MCF7, PC3, MGC-803 and EC109 was tested. Among them, compound 6p, showed strong anti-proliferative activities on esophageal carcinoma cells: EC9706 and EC109 with IC50 values of 1.09 ±â€¯0.03 and 2.79 ±â€¯0.45 µM, respectively. 6p also significantly induces both EC9706 and EC109 cell cycle arrest at G0/G1 phase and cell apoptosis, as well as intracellular ROS accumulation, which could be markedly reversed caspase or ROS inhibitor: NAC. Meanwhile, treatment of compound 6p results in significant declined mitochondria membrane potential, increases in the expression of P53 and bax, as well as decrease in Bcl-2. 6p also activates caspase-8/9/3, PARP and Bid, indicating that 6p induces cancer cell apoptosis via the death receptor-mediated extrinsic pathway and the mitochondria-mediated intrinsic pathway. Further studies also proved that 6p does not show obvious side effects at cellular and in vivo levels. Our findings suggested that hydrazone derivative: compound 6p may serve as a lead compound for further optimization against esophageal cancer cells.

Discovery of tranylcypromine analogs with an acylhydrazone substituent as LSD1 inactivators: Design, synthesis and their biological evaluation.

Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC50 = 91.83 nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1. Our findings indicated that compound 4q may serve as a potential leading compound to target LSD1 overexpressed gastric cancer.