Discovery of Benzo[cd]indol-2(1H)-ones and Pyrrolo[4,3,2-de]quinolin-2(1H)-ones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain with Potential High Efficiency against Acute Gouty Arthritis

Abstract

The bromodomain and extra-terminal domain (BET) family of proteins are readers which specifically recognize histone-acetylated lysine residues. Each BET bromodomain protein contains two highly homologous domains: the first bromodomain (BD1) and the second bromodomain (BD2). Pan-BET bromodomain inhibition is a potential therapy for various cancers and immune-inflammatory diseases, but only few reported inhibitors show selectivity within the BET family. Herein, we identified a series of benzo­[cd]­indol-2­(1H)-ones and pyrrolo­[4,3,2-de]­quinolin-2­(1H)-ones with good selectivity for BET BD1. Through structure-based optimization, highly active and selective compounds are ultimately obtained. The representative compounds are the first reported inhibitors with selectivity more than 100-fold for BRD4(1) over BRD4(2). Among them, we further show that 68 (LT052) mediates BRD4/NF-κB/NLRP3 signaling inflammatory pathways with comparable protein expression and significantly improves symptoms of gout arthritis in a rat model. Therefore, selective pharmacological modulation of individual bromodomains could represent a strategy for the treatment of acute gouty arthritis.

The BET family in immunity and disease

“…The pharmacological or genetic inhibition of BRD4 alleviates inflammatory response by inhibiting NLRP3 signaling pathways in varous conditions, such as in TNF-primed rat nucleus pulposus cells, 28 monosodium urate-induced acute gouty arthritis, 74 and middle cerebral artery occlusion-mediated glial activation. 75 Mechanistically, BRD4 inhibition decreases the expression of NLRP3 and CASP1 by limiting the transcriptional activity of RELA.…”

“…As mentioned above, it has been proved that the BRD4-NF-κB signaling pathway has a great contribution to the development of gout arthritis, diabetic intervertebral disc degeneration, osteoarthritis, and rheumatoid arthritis. 51,74,98,[175][176][177] Other diseases. BETs are also involved in other diseases due to their immunomodulatory and proinflammatory properties, such as spontaneous preterm birth, preeclampsia, retinal inflammatory disease, inherited retinal degeneration, age-related macular degeneration, and psoriasis.…”

Structural variation of protein–ligand complexes of the first bromodomain of BRD4

“…The pool of BRD4 inhibitors continues to grow, with most identified through fragment or structure-based drug design based on properties of known BRD4 inhibitors. [23][24][25][26][27] Additionally, a recent review 28 identified three novel strategies in targeting BRD4, including bivalent BRD4 inhibitors, proteolytic targeting chimeric molecules and re-purposing of kinase inhibitors. The selectivity of inhibitors is also being targeted.…”

Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout

“…Transcription factors mapping identified several transcription factors, some of which ( ATF2 , BRD4 , CEBPA, CEBPB, CLOCK , ELK4 , FOS , KLF6 , KLF9 , KMT2A ( MLL1 ), MED1 , NR1H4 ( FXR ), RELA ( p65 ), RUNX1 , RXR , SP1 , SPI1 ( PU.1 ), STAT1 , and VDR ) were reported in the literature to regulate IL-1β ( Figure S17 ). Furthermore, BRD4 was implicated in gouty inflammation in the past [ 43 ]. The involved signaling pathways of these transcription factors in gouty inflammation deserve further studies.…”