Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Donegan, Rebecca K.; Lieberman, Raquel L.

doi:10.1021/acs.jmedchem.5b00828

Cited by 53 publications

(59 citation statements)

References 280 publications

(596 reference statements)

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“…al (Waki et al, 2001) first reported that Rho kinase inhibition could lower IOP in rabbits via topical application and intracameral injections of Y-27632. Following this initial observation, several laboratories have confirmed that Y-27632 and other Rho kinase inhibitors consistently lower IOP in various animal models including rabbits, rodents, cats and monkeys, under both normal and ocular hypertensive conditions (Donegan and Lieberman, 2016; Feng et al, 2015; Fukunaga et al, 2009; Inoue and Tanihara, 2013; Isobe et al, 2014; Junglas et al, 2012; Li et al, 2016; Nishio et al, 2009; Pattabiraman et al, 2015b; Sumi et al, 2014; Van de Velde et al, 2014). Importantly, both ROCK1 and ROCK2 null mice exhibit lower basal IOP, confirming a definitive role for Rho kinase in IOP homeostasis (Whitlock et al, 2009).…”

Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 86%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

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Section: Role Of Rho/rho Kinase Signaling In the Conventional Ah Omentioning

confidence: 86%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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“…A contributor to TM dysfunction is TM cell death, 24,43 which can be brought about by the aggregation of mutant myocilin. 44 Nonsynonymous mutations in myocilin, localized to its olfactomedin domain, result in non-native tertiary structures, which promote facile aggregation and leads to TM cell death. 43,45 Recently, it was demonstrated that Grp94 associates with amyloid-like aggregates of mutant myocilin but cannot triage these aggregates for degradation through the ER-associated degradation (ERAD) pathway.…”

Section: Primary Open Angle Glaucoma and Grp94-selective Inhibitionmentioning

confidence: 99%

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

et al. 2016

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Glucose regulated protein 94 (Grp94) is the endoplasmic reticulum resident of the heat shock protein 90 kDa (Hsp90) family of molecular chaperones. Grp94 associates with many proteins involved in cell adhesion and signaling, including integrins, Toll-like receptors, immunoglobulins, and mutant myocilin. Grp94 has been implicated as a target for several therapeutic areas including glaucoma, cancer metastasis, and multiple myeloma. While 85% identical to other Hsp90 isoforms, the N-terminal ATP-binding site of Grp94 possesses a unique hydrophobic pocket that was used to design isoform-selective inhibitors. Incorporation of a cis-amide bioisostere into the radamide scaffold led to development of the original Grp94-selective inhibitor, BnIm. Structure–activity relationship studies have now been performed on the aryl side chain of BnIm, which resulted in improved analogues that exhibit better potency and selectivity for Grp94. These analogues also manifest superior antimigratory activity in a metastasis model as well as enhanced mutant myocilin degradation in a glaucoma model compared to BnIm.

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“…Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . [43][44][45] Clinical trials for glaucoma have ensued. 46 The effects of AR modulation on specific tissues in the eye and on intraocular pressure (IOP) have been extensively probed by multiple techniques.…”

Section: Ocular Purine Receptors As Drug Targets 539mentioning

confidence: 99%

Ocular Purine Receptors as Drug Targets in the Eye

Civan

2016

Journal of Ocular Pharmacology and Therapeutics

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Agonists and antagonists of various subtypes of G protein coupled adenosine receptors (ARs), P2Y receptors (P2YRs), and ATP-gated P2X receptor ion channels (P2XRs) are under consideration as agents for the treatment of ocular diseases, including glaucoma and dry eye. Numerous nucleoside and nonnucleoside modulators of the receptors are available as research tools and potential therapeutic molecules. Three of the 4 subtypes of ARs have been exploited with clinical candidate molecules for treatment of the eye: A 1 , A 2A , and A 3 . An A 1 AR agonist is in clinical trials for glaucoma, A 2A AR reduces neuroinflammation, A 3 AR protects retinal ganglion cells from apoptosis, and both A 3 AR agonists and antagonists had been reported to lower intraocular pressure (IOP). Extracellular concentrations of endogenous nucleotides, including dinucleoside polyphosphates, are increased in pathological states, activating P2Y and P2XRs throughout the eye. P2YR agonists, including P2Y 2 and P2Y 6 , lower IOP. Antagonists of the P2X7R prevent the ATP-induced neuronal apoptosis in the retina. Thus, modulators of the purinome in the eye might be a source of new therapies for ocular diseases.

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Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Cited by 53 publications

References 280 publications

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Development of Glucose Regulated Protein 94-Selective Inhibitors Based on the BnIm and Radamide Scaffold

Ocular Purine Receptors as Drug Targets in the Eye

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