Seneci Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

1. Auflage 2015
ISBN: 978-0-12-801959-7
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 260 Seiten

This book is a neurochemistry-based companion for Protein Misfolding and Neurodegenerative Diseases: Molecular Targets, an Elsevier title by the same author publishing in December 2014. While the first book focuses on biology and molecular targets, this companion book describes how these targets are regulated by small molecules and disease-modifying compounds. The book begins with a brief introduction to how key proteins become dysfunctional, and each subsequent chapter describes major disease mechanisms in Alzheimer's and other tauopathies. Properties and development status of these molecular targets and disease mechanisms are thoroughly described, as are small molecule effectors of autophagy and dis-aggregating agents. - Written to provide comprehensive coverage of neurodegenerative disease-modifying compounds - Provides discipline-specific chapters that cover medicinal chemistry and clinical applications - Provides an overview of more than 200 chemical classes and lead compounds, acting on selected molecular targets that are of relevance to any neurodegenerative disorder - Coverage of misfolding diseases, chaperone proteins, ubiquitination and autophagy/oncology makes this book suitable for structural neurochemists, chemists, biologists, non-CNS scientists, and scientists interested in drug discovery

Dr. Pierfausto Seneci is Associate Professor in the Department of Organic and Industrial Chemistry at the University of Milan. He is currently affiliated with the University of Milan Centre for Interdisciplinary Biomolecular Studies and Industrial Applications (CISI) Centre of Excellence, and is responsible for the Combinatorial Chemistry/High Throughput MedChem Laboratory. He has over 20 years of medicinal chemistry experience working in industry, and held business development positions with GSK, Sanofi, and start-up pharmaceutical companies including Sirenade and NiKem working in drug discovery, neurodegeneration, oncology, and antibacterials. He is author of approximately 80 papers on the topic and several book chapters, including the book 'Solid-Phase Synthesis and Combinatorial Technologies” with Wiley-Interscience in 2000.

Autoren/Hrsg.

Seneci, Pierfausto

Leseproben

Chapter 1 Chemical Modulators of Protein Misfolding, Neurodegeneration and Tau
What is not Covered Next
Abstract
This chapter covers a small number of putative disease-modifying compounds, acting either on tau or on amyloid ß (Aß). Their mechanism of action is either unknown or different from the extensively exemplified mechanisms of the compounds described in Chapters 2 to 6. Namely, the structure and biological properties of six modulators of tau post-translational modifications (PTMs, phosphorylation and glycosylation), and of stabilizers of the structure of microtubules (MTs), are reported as putative tau pathology modifiers. Three ?-secretase inhibitors (GSI) and modulators (GSM), and three neuroprotective-proneurogenic compounds acting on Aß peptides are also described. Their clinical characterization in studies on neurodegenerative disease (NDD) patients is thoroughly illustrated, as is the current status of research on each clinical candidate and on its analogues. Keywords
small molecules tau microtubules kinases O-GlcNAcylation ß amyloid ?-secretase inhibitors and modulators proneurogenic compounds Is this book comprehensive? I guess not. This is how the biology-oriented companion book [1] ends, and this is even truer at the end of this book. Here my task apparently was easier, as I planned to cover five pathways (chaperones (HSPs)/Chapter 2, ubiquitin proteasome system (UPS)/Chapter 3, autophagy/Chapter 4, aggrephagy/Chapter 5, anti-aggregation and disassembly of amyloidogenic proteins/Chapter 6) through the modulators of selected targets for each pathway (heat shock protein 27/Hsp27, Hsp70, Hsp90/Chapter 2; C-terminus of Hsc70 interacting protein/CHIP, ubiquitin-specific protease 14/USP14/Chapter 3; mammalian target of rapamycin complex 1/mTORC1/Chapter 4; p62, histone deacetylase 6/HDAC6/Chapter 5; tau antiaggregation and disassembly agents/Chapter 6). More than 250 compounds act on a mix of chemically validated (e.g., Hsp90, mTORC1, and tau aggregation inhibitors) and scarcely exploited targets (e.g., Hsp27, p62, and tau disassembly modulators). While writing the last words of Chapter 6, though, I realized that some well-characterized, putative disease-modifying compounds endowed with validated mechanisms of action against neurodegenerative disease (NDD) would have been missing. Is it right to cut them out just because their mechanism of action does not strictly comply with my selection rules? I believe that the right answer is no. Thus, I inserted an introductive “miscellaneous” chapter here, which makes this book a more complete chemistry-oriented description of misfolding and NDD. Twelve compounds acting on tau and Aß (respectively 1.1–1.6, Figure 1.1 and 1.7–1.11b, Figure 1.2) are thoroughly described in Chapter 1. While the focus of this book is unchanged, the most prospective putative disease-modifiers that do not act on targets covered in Chapters 2 to 6 are described here. Figure 1.1 Small molecule modulators of tau: chemical structures, 1.1–1.6. 1.1. Tau-targeted compounds
1.1.1. Tau Kinase Inhibitors
Decreasing tau hyperphosphorylation (HP) is a validated approach against tauopathies [2]. The serine-threonine glycogen synthase kinase 3 beta (GSK-3ß [3]) is among the most exploited kinase targets against Alzheimer’s disease (AD) and tauopathies, and GSK-3ß inhibitors have been clinically evaluated. A recent review [4] covers the use of small molecule GSK-3ß inhibitors in the central nervous system (CNS). Thiadiazolidinones (TDZDs) are the most promising synthetic adenosine triphosphate (ATP)-non-competitive GSK-3ß inhibitors [5]. 1-Naphthyl TDZD (tideglusib, 1.1, Figure 1.1) has been clinically developed against AD and tauopathies [6]. It interacts strongly and irreversibly with GSK-3ß, without covalently binding to the kinase [7]. It activates the peroxisome proliferator-activated receptor ? (PPAR?) nuclear receptor [8]. Tideglusib (200 mg/kg/daily, orally/p.o., 3 months) in a double amyloid precursor protein (APP) tau transgenic (TG) mouse model provides biochemical (reduction of tau phosphorylation at GSK-3ß epitopes, reduction of amyloid load) and functional efficacy (block of neuronal loss in AD-affected brain areas) [9]. Tideglusib is active in a double APP-presenilin (PSEN) TG model [10]. It increases the levels of neurotrophic peptide insulin growth factor 1 (IGF-1), and promotes endogenous hippocampal neurogenesis in vitro and in vivo through GSK-3ß inhibition [11]. Clinical trials with tideglusib show good tolerability (Phase I study, healthy volunteers, oral daily dosages between 50 and 1200 mg, up to 14 days) [12]. A Phase IIa study on 30 AD patients (400 to 1000 mg daily, p.o., 15 weeks) confirms the good tolerability of tideglusib and provides signs of efficacy in mild to moderate AD patients [11]. Two Phase IIb studies on AD (ARGO [13], 306 patients) and progressive supranuclear palsy (PSP, TAUROS [14], 146 patients) do not reach primary and secondary endpoints [15], although signs of reduced brain atrophy are observed in TAUROS patients [16]. Consequently, the development of tideglusib is stopped. Tau kinase inhibitors are not currently in clinical trials against AD or other tauopathies, although tau HP remains a validated and prospective therapeutic target. 1.1.2. Tau O-GlcNAcylation Enhancers
The modification of peptide hydroxy groups with N-acetylglucosamine (OGlcNAc, O-GlcNAcylation) is controlled by two enzymes. The O-GlcNAc transferase OGT [17] introduces a GlcNAc moiety on more than 500 protein substrates, including up to 11 Ser and Thr residues on tau. The O-GlcNAc hydrolase OGA [18] removes GlcNAc from the same residues/substrates in a dynamic equilibrium. O-GlcNAc dynamic cycling influences cell cycle control [19], development [20], signaling [21], and trafficking [22]. O-GlcNAcylation is a regulation mechanism in the brain, and deregulated O-GlcNAcylation is observed in neuronal disorders [23]. A hypo-O-GlcNAcylation/HP pattern is observed on tau in AD brain tissues [24]. Brain-targeted deletion of OGT in mice leads to tau HP and to neuronal death [20]. An increase in O-GlcNAcylation, through small molecule-mediated OGA inhibition in mice, results in a residue-specific reduced level of phosphorylation on tau [25] that does not perturb the microtubule (MT)–tau interaction [26]. Thus, an increase of O-GlcNAcylation on tau is a sound therapeutic goal. Either an increase in OGT activity or a decrease in OGA activity should increase tau O-GlcNAcylation. As enzyme inhibitors are more easily found and rationally designed than enzyme activators, OGA inhibitors seem to be a more achievable goal [27]. Most of them are OGlcNAc analogues, mimicking the substrate-assisted enzymatic mechanism of OGA [28]. The X-ray structure of complexes between human OGA homologues and OGA inhibitors [29] facilitate the rational design of selective OGA-targeted inhibitors [30]. The 2-aminothiazoline thiamet G (1.2, Figure 1.1) [31] is a rationally designed OGlcNAc mimic. Its 2-amino function increases its pKa, strengthens the interaction between thiamet G and OGA, improves its selectivity vs. structurally similar hydrolases, and increases its aqueous solubility and stability [31]. Thiamet G reduces tau phosphorylation in PC-12 cells at pathology-related Ser 396 and Thr231 residues. It crosses the blood–brain barrier (BBB) when administered p.o. to healthy rats at 200 mg/kg, and causes similar phosphoepitope reduction patterns [31]. Chronic treatment with thiamet G (500 mg/kg daily, p.o., 36 weeks) shows efficacy on P301L tau-expressing JNPL3 TG mice [32]. Its biochemical (increased motor neuron count, decreased neurofibrillary tangle (NFT) count, decreased neurogenic atrophy of skeletal muscle) and behavioral effects (increased body weight, improved rotarod and cage-hang performance) indicate neuroprotection devoid of toxic effects [32]. Brain samples from TG mice show a thiamet G-dependent increase of OGlcNAcylation, and a phosphorylation state-independent reduction of tau aggregation [32]. The recent agreement between a small biotech and a major pharmaceutical company [33] could lead to the clinical development of thiamet G-related OGA inhibitors as treatments against tauopathies. 1.1.3. Microtubule (MT)-binding Compounds
Tau toxicity stems from loss-of-function (LOF) and gain-of-function (GOF) of pathological tau species [34]. The latter element refers to pathological interactions...