A5101779684- Hepatitis C virus research
- Pharmacogenetics and Drug Metabolism
- Inflammatory mediators and NSAID effects
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- HIV Research and Treatment
- Cancer-related Molecular Pathways
- Machine Learning in Materials Science
- Drug Transport and Resistance Mechanisms
- Innovative Microfluidic and Catalytic Techniques Innovation
- Genomics and Rare Diseases
- Ubiquitin and proteasome pathways
- Metabolism, Diabetes, and Cancer
- Receptor Mechanisms and Signaling
- Protein Degradation and Inhibitors
- Liver Disease Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Biochemical and Molecular Research
- Pancreatic function and diabetes
- Synthesis and Reactions of Organic Compounds
- Hepatitis B Virus Studies
- Cancer Mechanisms and Therapy
- FOXO transcription factor regulation
- Quinazolinone synthesis and applications
- Advanced Breast Cancer Therapies
Research Triangle Park Foundation
2008-2021
GlaxoSmithKline (United States)
2008-2021
A well-characterized library of experimental kinase inhibitors provides leads for targeting the untargeted kinome. Despite success protein as approved therapeutics, drug discovery has focused on a small subset targets. Here we provide thorough characterization Published Kinase Inhibitor Set (PKIS), set 367 small-molecule ATP-competitive that was recently made freely available with aim expanding research in this field and an experiment open-source target validation. We screen activity assays...
Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry synthetic planning of small molecules; there are at least a few reports companies employing
We previously described the discovery of GSK5852 (1), a non-nucleoside polymerase (NS5B) inhibitor hepatitis C virus (HCV), in which an N-benzyl boronic acid was essential for potent antiviral activity. Unfortunately, facile benzylic oxidation resulted short plasma half-life (5 h) human volunteers, and backup program initiated to remove metabolic liabilities associated with 1. Herein, we describe second-generation NS5B inhibitors including GSK8175 (49), sulfonamide- N-benzoxaborole analog...
A series of imidazo[1,2-a]pyridines which directly bind to HCV Non-Structural Protein 4B (NS4B) is described. This demonstrates potent in vitro inhibition replication (EC50 < 10 nM), direct binding purified NS4B protein (IC50 20 and an resistance pattern associated with (H94N/R, V105L/M, F98L) that are unique among reported clinical assets, suggestive the potential for additive or synergistic combination other small molecule inhibitors replication.
We describe the preclinical development and in vivo efficacy of a novel chemical series that inhibits hepatitis C virus replication via direct interaction with viral nonstructural protein 4B (NS4B). Significant potency improvements were realized through isosteric modifications to our initial lead 1a. The temptation improve antiviral activity while compromising physicochemical properties was tempered by judicial use ligand efficiency indices during optimization. In this manner, compound 1a...
Kabuki Syndrome (KS) is a rare disorder characterized by distinctive facial features, short stature, skeletal abnormalities, and neurodevelopmental deficits. Previously, we showed that loss of function RAP1A, RAF1 regulator, can activate the RAS/MAPK pathway cause KS, an observation recapitulated in other genetic models disorder. These data suggested suppression this signaling cascade might be therapeutic benefit for some features KS. To pursue possibility, performed focused small molecule...