Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype

Abstract

R. K. (2020). Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype. Journal of Medicinal Chemistry.

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

“…Further chemical modification of compound 7 leads to another potent, selective, and cell-permeable inhibitor of BD1 (GSK789 ( 8 )), displaying more than 1000-fold selectivity for BD1 over BD2 and achieving a submicromolar inhibition of monocyte chemoattractant protein-1 (MCP-1) release in human whole blood (pIC 50 = 6.5) . Starting with I-BET151 guided by structural information leads to imidazoquinoline compound 9 with 150-fold BD1 selectivity over BD2 . Compound 9 reduces the production of IL-6 and MCP-1 in LPS-stimulated human peripheral blood mononuclear cells (PBMCs) and whole blood and suppresses MV4-11 lymphoblast leukemia cell growth (pIC 50 = 7.0), indicating that BD1-selective inhibitor compound 9 is sufficient to maintain the anti-inflammatory and antiproliferative activity of pan-BET inhibition.…”

Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

“…42,43 The therapeutic potential of pan-BD2 inhibition also extends beyond oncology as demonstrated by RVX-208 (Figure 1), a weak, biased pan-BD2 inhibitor, that is currently in phase III for cardiovascular indications. 26,38 We have recently reported our own effort toward the identification of drug-like selective BD1 37,44 or BD2 45−47 inhibitors and have characterized their impact on chromatin binding and their efficacy in in vitro and in vivo models of oncology and inflammation. 48 Regarding the discovery of BD2 selective inhibitors, we identified the two hits 1 and 2 by high throughput screening of the GSK compound collection (≈2 M compounds) which led, through a program of optimization, to the identification of potent and selective pan-BD2 selective inhibitors 3 (GSK620), 47 4 (GSK549), 47 and 5 (GSK046), 45 as shown in Figure 2, (BRD4 data used is representative of the other isoforms).…”

The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation

“…There have been many crystal structures of BRD4 complexed with various small-molecule inhibitors and apo-BRD4. 77–82 This provides useful structural information for designing novel inhibitors. However, the crystal structures of some inhibitors remain to be determined; therefore, molecular docking, which has been used for constructing the complex structure for inhibitor/protein systems, 83–85 was applied in this work.…”