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.

Synthesis and anti-gastric cancer activity evaluation of novel triazole nucleobase analogues containing steroidal/coumarin/quinoline moieties.

A series of novel triazole nucleobase analogues containing steroidal/coumarin/quinoline moieties have been synthesized based on copper-catalyzed azide-alkyne cycloaddition (CuAAC). The anti-cancer activity of the new triazole nucleobase analogues was studied in gastric cancer cell lines (MGC-803, SGC-7901) and normal gastric epithelial cells (GES-1) in vitro. Some of the synthesized compounds could significantly inhibit the proliferation of these tested cancer cells. Among the tested compounds, compound 20c demonstrated good anti-proliferation activity against MGC-803 cells (IC50 = 1.48 µM) and SGC-7901 (IC50 = 2.28 µM) cells as well as the best selectivity between the cancer and normal cells. Further mechanistic studies indicated that compound 20c could down-regulate the expression of TGF ß1 both in the tested gastric cancer cell lines and inhibit the cell migration and invasion. The results of the study indicate that compound 20c could be used as a promising skeleton for anti-gastric cancer agents with improved efficacy and less side effects.

Design, synthesis and biological evaluation of new steroidal ß-triazoly enones as potent antiproliferative agents.

ß-Triazoly enones are biologically interesting scaffolds, incorporation of such scaffolds into the steroid nucleus may generate new bioactive steroids and further enrich structural types of steroids. In this work, a series of new steroidal ß-triazoly enones were synthesized based on click chemistry and Claisen-Schmidt condensation reaction and further evaluated for their antiproliferative activity against a panel of cancer cells. Most of these compounds showed better potency against PC-3 and MGC-803 cells. Particularly, compound 5a inhibited PC-3 and MGC-803 cells potently with the IC50 values of 1.61 and 1.16 µM, respectively, and was less toxic toward GES-1 with an IC50 value of 20.72 µM. Further mechanistic studies showed that compound 5a inhibited migration and invasion of MGC-803 and PC-3 dose-dependently. Treatment with compound 5a varied mRNA levels and protein expression of EMT markers in both cells. Collectively, the steroidal ß-triazoly enones could be potentially utilized to develop new anticancer agents with the ability of inhibiting cell migration and invasion.