4-Br-Bnlm is a selective inhibitor of glucose-regulated protein 94 (Grp94) with an EC50 value of 0.96 µM. 4-Br-Bnlm reduces the levels of mutant myocilin proteins as well as wild-type myocilin misfold in cells. 4-Br-Bnlm promotes the clearance of toxic formsof myocilin and reduces myocilin toxicity[1][2].
4-Br-Bnlm (0-100 µM；24 h) 抑制了人胚肾 (HEK) 细胞中 1477N 突变心肌蛋白的表达[1]。
4-Br-Bnlm (30 µM；24 h) 降低了原代人小梁网 (HTM) 细胞的突变心肌素水平和毒性[1]。
4-Br-Bnlm (3、10 和 30 µM；24 h) 以剂量依赖性方式抑制肌球蛋白细胞中心肌素的分泌[1]。
4-Br-Bnlm (30 µM 和 100 µM；24 h) 不引起 HTM 细胞的热休克反应[2]。
Cell Viability Assay[1]
| Cell Line: | Primary human HTM cells. |
| Concentration: | 30 µM. |
| Incubation Time: | 24 h. |
| Result: | Significantly reduced the level of Y437H mutant myocilin without affecting WT myocilin and the RFP vector in HEK cells. |
Western Blot Analysis[1]
| Cell Line: | HEK cells. |
| Concentration: | 0, 1, 3, 10, 30 and 100 µM. |
| Incubation Time: | 24 h. |
| Result: | Significantly decreased 1477N mutant myocilin in HEK cells expression without causing the degradation of other Hsp90-dependent clients Akt and Ras. |
4-Br-Bnlm (300 µM；滴眼； 一天一次持续 12 周) 清除了 Tg-MYOCY437H 小鼠模型中小梁网 (TM) 细胞内的突变心肌，降低了眼内压。4-Br-Bnlm 改善了感光负反应 (PhNR) 缺陷[2]。
| Animal Model: | Tg-MYOCY437H mice[2]. |
| Dosage: | 300 µM. |
| Administration: | Eye drops; once daily for 12 weeks. |
| Result: | Inhibited mutant myocilin expression and restored the PhNR deficits. |
[1]. Stothert AR, et al, Fontaine SN, Crowley VM, Mishra S, Blagg BS, Lieberman RL, Dickey CA. Exploiting the interaction between Grp94 and aggregated myocilin to treat glaucoma. Hum Mol Genet. 2014 Dec 15;23(24):6470-80.
[2]. Stothert AR, et al. Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma. Sci Rep. 2017 Dec 20;7(1):17951.