A5102828266- Click Chemistry and Applications
- Protease and Inhibitor Mechanisms
- HIV Research and Treatment
- RNA Interference and Gene Delivery
- Signaling Pathways in Disease
- Adenosine and Purinergic Signaling
- HIV/AIDS drug development and treatment
- Clinical Nutrition and Gastroenterology
- Monoclonal and Polyclonal Antibodies Research
- Biopolymer Synthesis and Applications
- Animal Nutrition and Physiology
- Animal Genetics and Reproduction
- Phagocytosis and Immune Regulation
- Sperm and Testicular Function
- Immunodeficiency and Autoimmune Disorders
- Digestive system and related health
- Psoriasis: Treatment and Pathogenesis
- Tryptophan and brain disorders
- Enzyme function and inhibition
- Whipple's Disease and Interleukins
- Kidney Stones and Urolithiasis Treatments
- Infant Nutrition and Health
- Biochemical effects in animals
- Biotin and Related Studies
- Synthesis and Biological Evaluation
GlaxoSmithKline (United States)
2020-2021
AMAG Pharmaceuticals (United States)
2019
University of California, Irvine
2004-2005
We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through affinity selection previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded potent, low clearance lead 11. Although amorphous 11 was highly bio-available, crystalline poorly soluble and suffered disappointingly bio-availability because solubility-limited absorption. A...
Article29 January 2021Open Access Transparent process Development of a small molecule that corrects misfolding and increases secretion Z α1-antitrypsin David A Lomas Corresponding Author [email protected] orcid.org/0000-0003-2339-6979 UCL Respiratory, Rayne Institute, University College London, UK Search for more papers by this author James Irving orcid.org/0000-0003-3204-6356 Christopher Arico-Muendel GlaxoSmithKline, Cambridge, MA, USA Svetlana Belyanskaya Andrew Brewster Stevenage, Murray...
With current anti-HIV treatments targeting only 4 of the 15 HIV proteins, many potential viral vulnerabilities remain unexploited. We report small-molecule inhibitors HIV-1 protein Nef. In addition to expanding arsenal, against untargeted proteins could be used dissect key events in lifecycle. Numerous incompletely characterized interactions between Nef and cellular ligands, for example, present a challenge understanding molecular during progression AIDS. Assays with phage-displayed from...
Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition using antibodies proven as an effective treatment. Oral anti-IL17 therapies are attractive alternative option, several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery a novel class inhibitors, identified via DNA-encoded chemical library screen, their subsequent optimization to provide in vivo efficacious inhibitors. These new protein–protein...
Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis prompted an interest their role as modulators antitumor response tumor microenvironment. Here we illustrate outcomes extensive lead-generation campaign for identification inhibitors, focusing on results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput),...
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation toxic oxalate that results from reduced activity alanine–glyoxylate aminotransferase (AGXT) in primary hyperoxaluria (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series potent HAO1 inhibitors, represented by compounds 3–6. Compound 5 was further optimized via various structure–activity relationship (SAR) exploration methods 29, compound with improved potency and...
Rapid evolution of drug-resistant viruses renders essentially all small-molecule antiviral treatments ineffective. We demonstrate an in vitro library versus approach to identify small molecules targeting a broad spectrum HIV-1 Nef protein variants. The technique could provide more effective therapies. First, clinically derived allelic variants, termed allelome, was selected for function by binding ligands p53, actin, or p56lck. Next, inhibitors challenged the allelome competition assays. In...
Abstract Severe α 1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes accumulation of homopolymers mutant within endoplasmic reticulum hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake high throughput screen identify small molecules bind to, and stabilise -antitrypsin. The lead compound blocks polymerisation vitro , reduces intracellular increases secretion three-fold mammalian cells including an iPSC model...
Abstract Tumors utilize many different escape mechanisms to evade anti-tumor immune responses. Xios Therapeutics has screened X-Chem’s proprietary 200-billion molecule DNA-encoded library against several immuno-oncology (IO) targets addressing T-cell centric, myeloid immunity and onco-metabolite pathways. Adenosine, for example, is a potent immunosuppressive metabolite, the ecto-5-nucleotidase (a.k.a. CD73), which catalyzes conversion of AMP adenosine, rate limiting enzyme production...
Tumors utilize many different escape mechanisms to evade anti-tumor immune responses. Xios Therapeutics has screened X-Chem's proprietary 200-billion molecule DNA-encoded library against several immuno-oncology (IO) targets addressing T-cell centric, myeloid immunity and onco-metabolite pathways. Adenosine, for example, is a potent immunosuppressive metabolite, the ecto-5-nucleotidase (a.k.a. CD73), which catalyzes conversion of AMP adenosine, rate limiting enzyme production extracellular...