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A Phase 1, Open Label, Ascending Dose Study to Evaluate the Safety of BBC1501 Administered by Intravitreal Injection for Neovascular Age-Related Macular Degeneration (nAMD)

This open-label study is being conducted to evaluate the initial safety and tolerability of BBC1501 IVT in patients with nAMD. The primary objective of this study is to evaluate the safety and tolerability of 3 ascending doses of IVT BBC1501 in patients with nAMD. The secondary objective of this study is to exploratory of BBC1501 efficacy following 3 ascending dose of BBC1501 in nAMD patient.

开始日期2024-06-01

申办/合作机构

Benobio Co., Ltd.

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2

项与 Benobio Co., Ltd. 相关的文献（医药）

2023-10-01·Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

Novel molecule BBC0901 inhibits BRD4 and acts as a catabolic regulator in the pathogenesis of osteoarthritis.

Article

作者: Son, Min-Hee ; Yang, Siyoung ; Lee, Hyemi ; Lee, In-Hyun ; Park, Young-Sik ; Nam, Jiho ; Jang, Hahyeong ; Jeon, Jimin ; Eyun, Seong-Il

Osteoarthritis (OA) is induced by matrix degradation and inflammation mediated by bromo-domain-containing protein 4 (BRD4)-dependent catabolic factors. BRD4 acts as both a transcriptional regulator and an epigenetic reader. BBC0901 was identified as an inhibitor of BRD4 using a DNA-encoded library screening system. We aimed to demonstrate the effects of BBC0901 on OA pathogenesis by in vitro, ex vivo, and in vivo analyses. BBC0901 inhibited the expression of catabolic factors that degrade cartilage without significantly affecting the viability of mouse articular chondrocytes. Additionally, ex vivo experiments under conditions mimicking OA showed that BBC0901 suppressed extracellular matrix degradation. RNA sequencing analysis of gene expression patterns showed that BBC0901 inhibited the expression of catabolic factors, such as matrix metalloproteinases (MMPs) and cyclooxygenase (COX)2, along with reactive oxygen species (ROS) production. Furthermore, intra-articular (IA) injection of BBC0901 into the knee joint blocked osteoarthritic cartilage destruction by inhibition of MMP3, MMP13, COX2, interleukin (IL)6, and ROS production, thereby obstructing the nuclear factor kappa-light-chain-enhancer of activated B cell and mitogen activated protein kinase signaling. In conclusion, BBC0901-mediated BRD4 inhibition prevented OA development by attenuating catabolic signaling and hence, can be considered a promising IA therapeutic for OA.

Antioxidants

A Novel BD2-Selective Inhibitor of BRDs Mitigates ROS Production and OA Pathogenesis

Article

作者: Jeon, Jimin ; Lee, In-Hyun ; Lee, Hyemi ; Yang, Siyoung ; Choe, Jihye ; Son, Min-Hee ; Lim, Min Ju

Bromodomain and extra-terminal domain (BET) family proteins regulate transcription and recognize lysine residues in histones. Selective BET inhibitors targeting one domain have attracted attention because they maintain normal physiological activities, whereas pan (nonselective) BET inhibitors do not. Osteoarthritis (OA) is a joint disorder characterized by cartilage degeneration for which no treatment currently exists. Here, we investigated whether the selective inhibition of BET proteins is an appropriate therapeutic strategy for OA. We focused on the development and characterization of 2-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (BBC0906), a novel bromodomain 2 (BD2)-specific inhibitor designed to suppress OA progression. Using a DNA-encoded chemical library (DEL) screening approach, BBC0906 was identified because of its high affinity with the BD2 domain of BET proteins. BBC0906 effectively reduced reactive oxygen species (ROS) production and suppressed catabolic factor expression in chondrocytes in vitro. Moreover, in an OA mouse model induced by the destabilization of the medial meniscus (DMM), BBC0906 intra-articular injection attenuated cartilage degradation and alleviated OA. Importantly, BBC0906 selectively inhibits the BD2 domain, thus minimizing its potential side effects. We highlighted the therapeutic potential of targeting BET proteins to modulate oxidative stress and suppress cartilage degradation in OA. BBC0906 is a promising candidate for OA treatment, offering improved safety and efficacy.

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