A5047781046- Tryptophan and brain disorders
- Advanced Drug Delivery Systems
- Nanoparticle-Based Drug Delivery
- Drug Solubulity and Delivery Systems
- RNA Interference and Gene Delivery
- Pharmacological Receptor Mechanisms and Effects
- Ocular Surface and Contact Lens
- Bipolar Disorder and Treatment
- Glaucoma and retinal disorders
- Advancements in Transdermal Drug Delivery
- Receptor Mechanisms and Signaling
- Advanced biosensing and bioanalysis techniques
- Nanoplatforms for cancer theranostics
- Protein purification and stability
- Cellular transport and secretion
- Supramolecular Self-Assembly in Materials
- Retinoids in leukemia and cellular processes
- Neuroscience and Neuropharmacology Research
- Chemokine receptors and signaling
- Proteoglycans and glycosaminoglycans research
- Computational Drug Discovery Methods
- Crystallization and Solubility Studies
- Viral Infectious Diseases and Gene Expression in Insects
- Polymer Surface Interaction Studies
- Innovative Microfluidic and Catalytic Techniques Innovation
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2022
Duke University
2020
BioSurfaces (United States)
2016-2017
University of Michigan–Ann Arbor
2016-2017
University at Buffalo, State University of New York
2011
Ball State University
2002
Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia the pharmaceutical industry. Here, we describe discovery of a novel class highly potent IDO1 heme-displacing featuring unique bicyclo[1.1.1]pentane motif. Compound 1, evolving an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked desired pharmacokinetic profile due to extensive...
Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types cancers. However, low overall response rates often hamper the broad utility potential these breakthrough therapies. Combination therapy strategies currently under intensive investigation in clinic, including combination PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report discovery a class heme-binding featuring unique amino-cyclobutarene motif, which was discovered...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this compounds. Structure-based drug design strategic incorporation polarity enabled rapid improvement on potency, solubility, oxidative metabolic stability. Metabolite studies revealed that amide hydrolysis in D-pocket was...
Abstract Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated Keytruda. High levels of may lead to a depletion arginine within the tumor microenvironment, inhibiting immune response. Thus, arginase inhibition potential greatly enhance immunotherapy treatment. Discovering novel inhibitors was met several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and...
Abstract Activation of retinoic acid-inducible gene I (RIG-I) increases pro-inflammatory cytokine production, enhances antigen presentation, and promotes tumor cell apoptosis. Here we assessed the pharmacological activity a RIG-I agonist encapsulated in lipid nanoparticle B16F10 mouse syngeneic model. To probe whether additional pathways may complement agonism, tested our compound combination with anti-PD-1 anti-CTLA-4 immune checkpoint inhibitors. The was administered intratumorally (IT)...