New Treatments for Glaucoma

摘要 突变型肌球蛋白（MYOC）的聚集，一种在小梁细胞内质网（ER）中发现的蛋白质， 网状（TM）细胞，破坏眼房水的流出，引起眼内分泌增加。 眼压（IOP）、进行性视网膜神经节细胞（RGC）死亡和视神经变性，导致 原发性开角型青光眼（POAG），特征是不可逆转的视力丧失。约5%的POAG和35% 的青少年开角型青光眼（JOAG）患者表现出由突变型青光眼的聚集驱动的青光眼， MYOC的形式。我们的研究小组确定了内质网（ER）驻留的Hsp 90亚型，葡萄糖- 调节蛋白94（Grp 94），如突变体肌球蛋白聚集体的组装所必需的。事实上，我们的团队 证明Grp 94抑制剂在体内有效治疗这种遗传性青光眼。有趣的是，Grp 94 抑制还可防止类固醇引起的IOP;这是一种导致继发性类固醇诱导的IOP升高的疾病。 青光眼（SIG）。这些数据表明Grp 94抑制剂具有治疗任何开角型青光眼的潜力。 目前的青光眼治疗，如β受体阻滞剂和前列腺素类似物，仅治疗青光眼的症状。 疾病，而不是根本原因。我们通过抑制Grp 94的方法，代表了一个独特的机会， 治疗突变MYOC驱动的POAG，并允许患有SIG的人维持其类固醇方案 而不牺牲他们的视力该申请旨在获得用于优化Grp 94抑制剂的资金， 改善选择性，调节适于眼部给药的物理化学性质，和 在动物模型中对优化的候选物进行临床前评价。大学的初步工作 圣母大学和佛罗里达大学已经确定，通过滴眼液选择性抑制Grp 94可以 提供了一种安全有效的治疗选择，通过利用 与目前可用的药剂不同的作用，可能无不良反应。在第一阶段，Grannus 将优化Grp 94的功效、相对于其他Hsp 90亚型的选择性以及物理化学性质 抑制剂使用合理的，基于结构的方法来构建新的先导化合物。目标1.合成 使用从共晶结构的溶液和先前的溶液中收集的数据合理设计Grp 94抑制剂， 构效关系研究。工作假设是构象约束的引入 和不同的官能团进入当前的Grp 94选择性抑制剂支架将增加选择性（超过 其它Hsp 90同种型）、结合亲和力和所设计类似物的药物样性质。目标2.评价 目的1中制备的Grp 94抑制剂在肌球蛋白聚集的体外模型中的有效性。有效 将对化合物进行额外的体内功效、安全性和分布测量分析 实验在完成拟议的工作后，我们将确定一种先导化合物， 药代动力学和药效学特征，以进一步进入IND使能研究。的结果 II期将用于完成IND申请，随后启动临床研究。

Abstract Aggregation of mutated myocilin (MYOC), a protein found in the endoplasmic reticulum (ER) of trabecular meshwork (TM) cells, disrupts the outflow of aqueous humor from the eye, causing increase in intraocular pressure (IOP), progressive retinal ganglion cell (RGC) death, and degeneration of the optic nerve, leading to primary open-angle glaucoma (POAG), characterized by irreversible vision loss. About 5% of POAG and 35 % of juvenile open-angle glaucoma (JOAG) patients exhibit glaucoma that is driven by the aggregation of mutant forms of MYOC. Our research team identified the endoplasmic reticulum (ER)-residing Hsp90 isoform, glucose- regulated protein 94 (Grp94), as necessary for the assembly of mutant myocilin aggregates. In fact, our group demonstrated that Grp94 inhibitors are effective in vivo to treat this hereditary glaucoma. Interestingly, Grp94 inhibition also prevents the IOP driven by steroids; a condition that leads to a secondary steroid-induced glaucoma (SIG). These data suggest that Grp94 inhibitors have the potential to treat any open-angle glaucoma. Current glaucoma treatments, such as beta blockers and prostaglandin analogs, only treat the symptoms of the disease and not the underlying cause. Our approach through Grp94 inhibition, represents a unique opportunity to treat mutant MYOC-driven POAG and allow persons afflicted with SIG to maintain their steroid regimens without sacrificing their vision. This application aims to secure funds for the optimization of Grp94 inhibitors to improve selectivity, modulation of physicochemical properties that are appropriate for ocular administration, and conduct pre-clinical evaluation of the optimized candidates in animal models. Preliminary work at the University of Notre Dame and the University of Florida has established that selective inhibition of Grp94 via eye drops can offer a safe and effective therapeutic option to treat hereditary forms of glaucoma by utilizing a mechanism of action that differs from currently available agents, potentially without adverse effects. In this Phase 1, Grannus will optimize the efficacy, selectivity over other Hsp90 isoforms, and the physicochemical properties of Grp94 inhibitors using a rational, structure-based approach to construct a new lead compound. Aim 1. Synthesis of rationally designed Grp94 inhibitors using the data gathered from solution of the co-crystal structures and prior structure-activity relationship studies. The working hypothesis is that introduction of conformational constraint and different functional groups into current Grp94-selective inhibitor scaffolds will increase the selectivity (over other Hsp90 isoforms), binding affinity, and drug-like properties of the designed analogs. Aim 2. Evaluate the Grp94 inhibitors prepared in Aim 1 for their effectiveness in in vitro models of myocilin aggregation. Effective compounds will undergo additional analyses for in vivo efficacy, safety and distribution measurement experiments. Upon completion of the proposed work, we will have identified a lead compound with improved pharmacokinetic and pharmacodynamic profile to progress further into IND-enabling studies. The results from Phase II will serve toward completion of an IND-application and subsequently, initiation of clinical studies.