A5037452839- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Cancer-related molecular mechanisms research
- RNA modifications and cancer
- PI3K/AKT/mTOR signaling in cancer
- Asthma and respiratory diseases
- Neuroscience and Neuropharmacology Research
- Cancer-related gene regulation
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Phenothiazines and Benzothiazines Synthesis and Activities
- RNA Research and Splicing
- Synthesis and Reactivity of Heterocycles
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Eosinophilic Disorders and Syndromes
- Quinazolinone synthesis and applications
- Pharmacological Receptor Mechanisms and Effects
- Amino Acid Enzymes and Metabolism
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Inhalation and Respiratory Drug Delivery
- RNA regulation and disease
- Receptor Mechanisms and Signaling
Charles River Laboratories (United Kingdom)
2019-2024
Servier (France)
2023
Mission Therapeutics (United Kingdom)
2021
MSD (UK) Limited (United Kingdom)
2005-2010
Merck & Co., Inc., Rahway, NJ, USA (United States)
2005-2006
University of Southampton
1994
N 6 -methyladenosine (m A) is an abundant internal RNA modification, influencing transcript fate and function in uninfected virus-infected cells. Installation of m A by the nuclear methyltransferase METTL3 occurs cotranscriptionally; however, genomes some cytoplasmic viruses are also A-modified. How cellular modification machinery impacts coronavirus replication, which exclusively cytoplasm, unknown. Here we show that replication SARS-CoV-2, agent responsible for COVID-19 pandemic, a...
Abstract Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity cancer cells remains a priority. Using novel enzymatic inhibitor RNA methyltransferase METTL3, we demonstrate global decrease in N6-methyladenosine (m6A) results double-stranded (dsRNA) formation and profound cell-intrinsic interferon response. Through unbiased CRISPR screens, establish dsRNA-sensing signaling are...
A series of high-affinity GABA(A) agonists with good oral bioavailability in rat and dog functional selectivity for the GABA(A)alpha2 -alpha3 subtypes is reported. The 7-trifluoromethylimidazopyrimidine 14g 7-propan-2-olimidazopyrimidine 14k are anxiolytic both conditioned unconditioned animal models anxiety minimal sedation observed at full BZ binding site occupancy.
Using an iterative structure-activity relationship driven approach, we identified a CNS-penetrant 5-(trifluoromethyl)-1,2,4-oxadiazole (TFMO, 12) with pharmacokinetic profile suitable for probing class IIa histone deacetylase (HDAC) inhibition in vivo. Given the lack of understanding endogenous HDAC substrates, developed surrogate readout to measure compound effects vivo, by exploiting >100-fold selectivity 12 exhibits over I/IIb HDACs. We achieved adequate brain exposure mice estimate...
Huntington's disease (HD) is a lethal autosomal dominant neurodegenerative disorder resulting from CAG repeat expansion in the huntingtin (HTT) gene. The product of translation this gene highly aggregation-prone protein containing polyglutamine tract >35 repeats (mHTT) that has been shown to colocalize with histone deacetylase 4 (HDAC4) cytoplasmic inclusions HD mouse models. Genetic reduction HDAC4 an model resulted delayed aggregation mHTT, along amelioration neurological phenotypes and...
Pim kinases have been targets of interest for a number therapeutic areas. Evidence durable single-agent efficacy in human clinical trials validated kinase inhibition as promising approach multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), potent, orally bioavailable, and well tolerated pan-Pim inhibitor that proved efficacious RPMI8226 MM.1S xenograft mouse models has evaluated an early development candidate.
Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular animal models Huntington's disease (HD), suggesting selective inhibition ATM could provide a novel clinical intervention to treat HD. Here, we describe development characterization inhibitor molecules enable vivo proof-of-concept studies HD models. Starting from previously reported inhibitors, aimed with few...
The development of a series GABAA α2/α3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery 16, remarkably α3-selective compound ideal for in vivo study. These ligands are antagonists at α1 subtype, good CNS penetration and receptor occupancy, excellent oral bioavailability.
Amalgamation of the structure-activity relationship two series GlyT1 inhibitors developed at Merck led to discovery a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy transporters rhesus monkey as determined by displacement PET tracer ligand.
Aiming at the inhaled treatment of pulmonary diseases, optimization process previously reported MAPI compound 92a is herein described. The project was focused on overcoming chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats order to be confident clinical effect without having overdose one biological targets. strategy based fine-tuning substitution pattern muscarinic PDE4 structural portions dual pharmacology compounds, also making use analysis...
Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important involved with autophagy. Given impaired autophagy been proposed pathogenic mechanism neurodegenerative diseases such HD, achieving Vps34 became...
Time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes may incur serious undesirable drug–drug interactions and in rare cases drug-induced idiosyncratic toxicity. The reactive metabolites are often generated through multiple sequential biotransformations form adducts with CYP to inactivate their function. complexity these processes makes addressing TDI liability very challenging. Strategies mitigate therefore highly valuable discovering safe therapies benefit patients. In this...
The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β2 agonists (MABAs) promises to be an excellent opportunity reduce formulation issues boost efficacy through cross-talk allosteric interactions. Herein, we report the results our drug discovery campaign aimed at improving therapeutic index a previous MABA series by exploiting super soft-drug concept. incorporation metabolic liability, stable site administration but undergoing rapid...
Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, frequent exacerbators, corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist β
In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for inhaled treatment pulmonary diseases. The identification was enabled by intuition that fusion a PDE4 scaffold derived from our CHF-6001 series with muscarinic through common linking ring could generate active versus both transmembrane receptor and intracellular enzyme. Two chemical characterized two different scaffolds were investigated. SAR optimization aimed at obtaining nanomolar affinity...
<div>Abstract<p>Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity cancer cells remains a priority. Using novel enzymatic inhibitor RNA methyltransferase METTL3, we demonstrate global decrease in N6-methyladenosine (m6A) results double-stranded (dsRNA) formation and profound cell-intrinsic interferon response. Through unbiased CRISPR screens, establish...