Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis

Abstract

Bromodomain containing protein 4 (BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases, including cancer, cardiac remodeling and heart failure. Herein, we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library (enamine). Then, structure–activity relationship (SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified compound C-34, which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells, compared to the positive control JQ1. Using computer-based molecular docking and cellular thermal shift assay, we further verified that C-34 could target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo , which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF- β 1/Smad2/3 signaling pathway. Taken together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease.

Structure-Based Discovery and Biological Assays of a Novel PRMT5 Inhibitor for Non-Small Cell Lung Cancer

“…Molecular docking [ 38 ] is a mature analytical method focusing on the analysis of protein ligands, which predicts the binding mode and affinity based on the 3D protein structure, and has recently been used to study new inhibitors [ 39 ]. The binding mode of 3039-0164 with PRMT5-SAM is shown in Figure 2 b, with a docking score of −8.51 kcal/mol.…”

Discovery of a Bromodomain and Extra Terminal Domain (BET) Inhibitor with the Selectivity for the Second Bromodomain (BD2) and the Capacity for the Treatment of Inflammatory Diseases

“…azepino [4,3,2-cd]isoindol-2-one (24). The preparation of compound 24 was similar to that of compound 10 to afford the title compound as a yellow solid (98 mg, 0.25 mmol, 42% yield).…”

“…On the other hand, introducing various substitutions at position 3 of the benzene ring produced contrasting results. Substituting an electronwithdrawing group (23−26), including cyano (23), nitro (24), trifluoromethyl (25), and trifluoromethoxy (26), significantly weakened potency against BRD4 BD2. However, substitution of an electron-donating group (27−29), including methyl (27), methoxy (28), and amino (29), resulted in an increase in potency against BRD4 BD2.…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…In addition, the promising molecule C-34 exhibits effective BRD4 inhibitory activity. The novel BRD4 inhibitor C-34 silences the downstream target c-MYC and further inhibits the TGF-β1/Smad2/3 signaling pathway, alleviating CFs activation in vitro and cardiac fibrosis in vivo [ 71 ]. The anti-fibrotic effects of BET inhibitors are promising for alleviating cardiac dysfunction and fibrosis [ 99 , 100 ].…”

“…This study provides new perspectives on the plasticity and specificity of BET-dependent regulation in tissue fibroblasts and also provides new trans- and cis-targets for the treatment of fibrotic diseases [ 100 ]. Consequently, the development of drugs targeting BET will hopefully bring new light to the treatment of cardiac fibrosis [ 71 ] ( Figure 3 ).…”