Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9,Drugs in R&D

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Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9
Drugs in R&D ( IF 2.2 ) Pub Date : 2022-04-29 , DOI: 10.1007/s40268-022-00389-0
Theodore J Kottom ₁ , Kyle Schaefbauer ₁ , Eva M Carmona ₁ , Eunhee S Yi ₂ , Andrew H Limper ₁

Affiliation

Background

The caspase recruitment domain-containing protein 9 (CARD9) inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis β-glucan-induced proinflammatory signaling, suggesting its viability as a candidate for preliminary anti-Pneumocystis drug testing in the rodent Pneumocystis pneumonia (PCP) model.

Methods

Mice were injected intraperitoneally (IP) daily with either vehicle or BRD5529 at 0.1 or 1.0 mg/kg for 2 weeks. Mouse weights were taken daily. At day 14, mice were euthanized, weighed, and analyzed by flexiVent™ for lung stiffness. Lungs, liver, and kidney were then harvested for hematoxylin and eosin (H&E) staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines via enzyme-linked immunosorbent assay (ELISA) and extracellular matrix generation via quantitative polymerase chain reaction (qPCR). Blood collection postmortem was performed for blood chemistry analysis. Furthermore, administration of BRD5529 prior to the intratracheal inoculation of fungal β-glucans, which are known proinflammatory mediators via the Dectin-1-CARD9 pathway, resulted in significant reductions in lung tissue interleukin-6 and tumor necrosis factor-α, suggesting the exciting possibility of the use of this CARD9 inhibitor as an additional therapeutic tool in fungal infections.

Results

BRD5529 at both IP doses resulted in no significant changes in daily or final weight gain, and analysis of lung stiffness by flexiVent™ showed no significant differences between the groups. Furthermore, ELISA results of proinflammatory cytokines showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups, as well as subsequent pathology scoring, showed no significant change. Blood chemistry analysis revealed similar, non-significant patterns.

Conclusions

In our initial general safety and toxicology assessments, BRD5529 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.

中文翻译：

CARD9 选择性抑制剂 BRD5529 的临床前和毒理学研究

背景

含半胱天冬酶募集结构域的蛋白 9 (CARD9) 抑制剂 BRD5529 已被证明是肺孢子虫β-葡聚糖诱导的促炎信号传导的有效体外抑制剂，表明其作为啮齿动物肺孢子虫初步抗肺孢子虫药物测试的候选者的可行性肺炎（PCP）模型。

方法

每天给小鼠腹膜内 (IP) 注射媒介物或 BRD5529，剂量为 0.1 或 1.0 mg/kg，持续 2 周。每天称量小鼠体重。第 14 天，对小鼠实施安乐死、称重并通过 FlexiVent™ 分析肺硬度。然后收获肺、肝和肾进行苏木精和伊红（H&E）染色和病理学评分。通过酶联免疫吸附测定 (ELISA) 进一步分析肺样本中的促炎细胞因子，并通过定量聚合酶链反应 (qPCR) 生成细胞外基质。进行死后血液采集以进行血液化学分析。此外，在气管内接种真菌 β-葡聚糖（已知通过 Dectin-1-CARD9 途径产生的促炎介质）之前给予 BRD5529，导致肺组织白细胞介素 6 和肿瘤坏死因子 α 显着减少，这表明令人兴奋的结果使用这种 CARD9 抑制剂作为真菌感染的额外治疗工具的可能性。

结果

两种腹腔注射剂量的 BRD5529 均未导致每日或最终体重增加发生显着变化，并且通过 FlexiVent™ 对肺硬度进行的分析显示，各组之间没有显着差异。此外，促炎细胞因子的 ELISA 结果显示各组之间没有重大差异。细胞外基质转录物的 qPCR 分析在统计学上相似。所有组的肺、肝、肾的H&E切片的检查和病理评分以及随后的病理评分均未显示显着变化。血液化学分析显示出类似的、不显着的模式。