LT052, a highly active and selective BET BD1 inhibitor with an IC50 of 87.7 nM, demonstrates nanomolar BRD4 BD1 potency and significant selectivity, being 138-fold more selective for BRD4 BD1 over BRD4 BD2 (IC50 =12.130 μM). Its anti-inflammatory properties make it a potential candidate for acute gout arthritis research [1].

BRDT BD1:357.1 nM, BRD4 BD1:87.7 nM, BRPF1B:567.5 nM, BRD3 BD1:246.3 nM

LT052, at a concentration of 1 μM, effectively suppresses NF-κB transcriptional activity in HUVECs cells and significantly reduces nitric oxide (NO) production by 101.89% in RAW264.7 cells. When assessing its in vitro anti-inflammatory potential, LT052 demonstrates equivalent or superior efficacy to the pan-BET inhibitor JQ1, despite JQ1's relatively modest protein activity performance. Furthermore, LT052 exhibits potent inhibitory effects on BRD4(1) with an IC50 value of 87.7±4.9 nM, BRD3(1) at 246.3±20.2 nM, BRDT(1) at 357.1±8.3 nM, and also impacts BRPF1b with an IC50 of 567.5±16.9 nM. Notably, LT052 displays a marked 238-fold preference for BD1 over BD2, showing binding affinities (Kd) of 105 nM for BD1 and >25 μM for BD2. Additionally, a 1-hour exposure to 1 μM LT052 disrupts MSU-induced pyroptosis in THP-1 cells by interfering with the BRD4/NF-κB/NLRP3 signaling pathways.

LT052, administered at 1 mg/kg via intra-articular injection, effectively mitigates synovial hyperplasia and severe neutrophil infiltration, proving to be a potent therapeutic agent for MSU-induced acute gouty arthritis. Furthermore, it inhibits macrophage pyroptosis in rat synovial tissues by modulating the BRD4/NF-κB/NLRP3 signaling pathway. Its clearance rate in liver microsomes across various species (human, monkey, dog, rat) ranges from 93.517 μL/min/mg to 146.685 μL/min/mg proteins, indicating a moderate stability in in vitro liver microsomal metabolism. The use of LT052 in male adult Sprague-Dawley rats (250-280 g) as acute gouty arthritis animal models restored joint circumference to normal levels.