D. Martin Watterson

Dual Inhibitors of p38α Mitogen-Activated Protein Kinase and Butyrylcholinesterase for the Modulation of Neuroinflammation and Cognitive Dysfunction

Damijan Knez, David Maliňák, A. Meden, Svit Ferjančič Benetik et autres

Chronic neuroinflammation and cholinergic dysfunction are major contributors to cognitive decline in Alzheimer's disease. Here, we report a series of pyridazine-based multitarget-directed ligands that simultaneously inhibit human butyrylcholinesterase (hBChE) and p38α mitogen-activated protein kinase (p38α MAPK). Pyridazines 8 and 21 were identified …

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The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer’s Disease Mouse Model

Erica Acquarone, Saktimayee M. Roy, Agnieszka Staniszewski, D. Martin Watterson et autres

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients …

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Discovery of small molecule candidate therapeutics against neuroimmune targets in Alzheimer’s disease

Linda Jo Van Eldik, Saktimayee M. Roy, Ottavio Arancio, D. Martin Watterson

BACKGROUND: Dysregulated brain inflammation is a critical mechanism driving neurodegenerative disease progression. Neuroinflammatory processes are fundamental to CNS homeostasis, but inflammation that is inefficient, excessive, or prolonged is detrimental. Stressor-induced proinflammatory cytokine overproduction is an explicit form of neuroinflammation linked to activated …

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USP22 drives tumor immune evasion and checkpoint blockade resistance through EZH2-mediated epigenetic silencing of MHC-I

Kun Liu, Radhika Iyer, Yi Li, Jun Zhu et autres

While immune checkpoint blockade (ICB) therapy has revolutionized the antitumor therapeutic landscape, it remains successful in only a small subset of patients with cancer. Poor or loss of MHC-I expression has been implicated as a common mechanism of ICB resistance. Yet, the …

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The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer’s Disease Mouse Model

Erica Acquarone, Saktimayee M. Roy, Agnieszka Staniszewski, D. Martin Watterson et autres

1. ABSTRACT Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic and neuronal loss underlies the decline in cognition and daily functioning, often accompanied by behavioral and psychological symptoms. Among these, neuropsychiatric disturbances such …

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Human p38 ALPHA MAPK:MW164 pyridazine inhibitor complex

J.S. Brunzelle, L. Shuvalova, Sophie Roy, D. Martin Watterson

Identification of p38 MAPK inhibition as a neuroprotective strategy for combinatorial SMA therapy

María J. Carlini, Jorge Espinoza‐Derout, Meaghan Van Alstyne, Sarah Tisdale et autres

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the SMN protein. The identification of disease modifiers is key to understanding pathogenic mechanisms and broadening the range of targets for developing SMA therapies that complement SMN upregulation. Here, …

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Crystal Structure of Human P38 alpha MAPK in Complex with MW01-21-114SRM

G. Minasov, J.S. Brunzelle, S. Roy, D. Martin Watterson et autres

Abstract 2473 Leveraging the Privileged Pyridazine Chemotype Using Informatics and Structure Assisted Fragment Expansion for CNS Protein Kinase Inhibitor Design: A Bench to Clinic Case Study

Saktimayee M. Roy, L. Shuvalova, J.S. Brunzelle, G. Minasov et autres

Diazines such as pyrimidine, pyrazine and pyridazine are chemotypes frequently found as the core of biologically important small molecules in nature and synthetic chemistry development of pharmaceuticals, agrochemicals and biomaterials. Due to the diversity of biological and material science functions generated by …

Bench to Bedside Using the iSAFE Discovery and Development Platform for CNS Protein Kinase Inhibitors: A Phase 2 Clinical Asset Example (Abstract ID: 170677)

Saktimayee M. Roy, L. Shuvalova, G. Minasov, J.S. Brunzelle et autres

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Optimized 5‐HT 2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction

Saktimayee M. Roy, Erica Acquarone, Elentina K. Argyrousi, Hong Zhang et autres

Abstract INTRODUCTION Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non‐pharmacological treatments. Cognitive or behavioral disturbances occur at …

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The 5HT2b Receptor in Alzheimer’s Disease: Increased Levels in Patient Brains and Antagonist Attenuation of Amyloid and Tau Induced Dysfunction

Erica Acquarone, Elentina K. Argyrousi, Ottavio Arancio, D. Martin Watterson et autres

BACKGROUND: Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues …

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