Abstract
Bromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.
Highlights
Osteoporosis is a type of skeletal disorder characterised by damaged bone quality and elevated risk of fracture, reducing the life quality of older adults and aggravating social burdens [1]
Compound (+)-ND is a potent suppressor for both Bromodomain-containing protein 4 (BRD4) and osteoclast formation Improvement of pharmacological activities is related to physicochemical properties and membrane permeability of compounds [17, 18]
The HTRF assays showed that introducing of dimethyl amine leading to better BRD4 (BD1) inhibitory efficacy with ~20-fold improvement of in vitro potency over (+)-JQ1 (Fig. 1D)
Summary
Osteoporosis is a type of skeletal disorder characterised by damaged bone quality and elevated risk of fracture, reducing the life quality of older adults and aggravating social burdens [1]. Abnormal osteoclast activity may disrupt bone remodelling, leading to osteopenic diseases [3, 4]. Administration of agents that suppress abnormal osteoclast activity could be an effective therapeutic strategy for osteoprotection. Epigenetics involves heritable alterations in cellular phenotype or gene expression, which are not associated with underlying alterations of gene code. Epigenetic modulators, such as histone deacetylation, DNA modifications by methylation, and non-coding RNA, play a pivotal role in bone metabolic disorders [5]. It is closely related to the regulation of gene transcription and mediates the expression of transcription genes associated with carcinomas [7, 8]. Dysfunction of BRD4 is correlated with development of bone-related diseases, and recent studies have reported the therapeutic efficacy of specific BRD4 inhibitors in bone-related diseases [9, 10]
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