A5010409671- Gastrointestinal Tumor Research and Treatment
- Antibiotic Resistance in Bacteria
- Cytokine Signaling Pathways and Interactions
- Synthetic Organic Chemistry Methods
- Cancer Mechanisms and Therapy
- Quantum Mechanics and Applications
- Chemokine receptors and signaling
- Multiple Myeloma Research and Treatments
- Glutathione Transferases and Polymorphisms
- Catalytic Alkyne Reactions
- Cyclopropane Reaction Mechanisms
- Sarcoma Diagnosis and Treatment
- Chronic Lymphocytic Leukemia Research
- Bacterial Genetics and Biotechnology
- Phagocytosis and Immune Regulation
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Random Matrices and Applications
- Synthesis and Catalytic Reactions
- Pneumocystis jirovecii pneumonia detection and treatment
- CRISPR and Genetic Engineering
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Science, Research, and Medicine
- Protein Degradation and Inhibitors
Pfizer (United States)
2012-2024
UPMC Hillman Cancer Center
2009-2023
Cellular Research (United States)
2023
National Institutes of Health
2009-2021
Cellectar Biosciences (United States)
2021
Arizona State University
2020
National Cancer Institute
2017
Center for Cancer Research
2017
University of Pittsburgh
2010-2015
KU Leuven
2014
Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target clinical immunosuppression. We report the development a specific, orally active inhibitor JAK3, CP-690,550, that significantly prolonged survival in murine model heart transplantation and cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On basis these preclinical results, we...
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading ubiquitination subsequent degradation of the target. They present exciting opportunity modulate proteins in manner independent enzymatic or signaling activity. As such, they have recently emerged as attractive mechanism explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding parameters...
There is a critical need for safer and more convenient treatments organ transplant rejection autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells involved the signaling of multiple cytokines important various T cell functions. Blockade JAK1/JAK3-STAT pathway with small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library screened against catalytic domain JAK3 resulting...
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy can result from silencing of enzymatic activity until protein resynthesis occur, along with potential increased selectivity targeting uniquely positioned nucleophilic residues protein. However, covalent approaches carry additional risk toxicities or hypersensitivity reactions modification unintended targets. Here we describe methods measuring reactivity reactive groups (CRGs) a biologically...
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells level that could not be achieved previously without such potency selectivity. In vitro, inhibits Th1 Th17 cell differentiation function, vivo it reduces disease pathology rat adjuvant-induced arthritis as well mouse...
We have investigated the molecular features of recombinant membranes that are necessary for photochemical function rhodopsin. The magnitude metarhodopsin I to II phototransient following a 25% +/- 3% bleaching flash was used as criterion activity at 28 degrees C and pH 7.0. Nativelike rhodopsin can be reconstituted with an extract total lipids from rod outer segment membranes, demonstrating protein is minimally perturbed by reconstitution protocol. Rhodopsin enhanced phosphatidylethanolamine...
Janus kinases (JAKs) are intracellular tyrosine that mediate the signaling of numerous cytokines and growth factors involved in regulation immunity, inflammation, hematopoiesis. As JAK1 pairs with JAK2, JAK3, TYK2, a JAK1-selective inhibitor would be expected to inhibit many inflammation immune function while avoiding inhibition JAK2 homodimer regulating erythropoietin thrombopoietin signaling. Our efforts began tofacitinib, an oral JAK approved for treatment rheumatoid arthritis. Through...
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator transcription (STAT) pathway. JAK1 for γ-common chain cytokines, interleukin (IL)-6, type-I interferon (IFN) family, while TYK2 in addition to IFN also plays a role IL-23 IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or inhibitors has demonstrated efficacy Phase III psoriasis, psoriatic arthritis,...
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during past 2 decades, identification highly selective JAK3 eluded scientific community. A within our research organization resulted first orally active specific inhibitor, which achieves isoform specificity through covalent interaction with a unique residue Cys-909. The relatively rapid...
Understanding the conformational ensemble of an intrinsically disordered protein (IDP) is great interest due to its relevance critical intracellular functions and diseases. It now well established that polymer scaling behavior can provide a deal information about properties as liquid–liquid phase separation IDP. is, therefore, extremely desirable be able predict IDP's from sequence itself. The work in this direction so far has focused on highly charged proteins how charge patterning perturb...
ABSTRACT Multidrug resistance in Gram-negative bacteria has become so threatening to human health that new antibacterial platforms are desperately needed combat these deadly infections. The concept of siderophore conjugation, which facilitates compound uptake across the outer membrane by hijacking bacterial iron acquisition systems, received significant attention recent years. While standard vitro MIC and frequency methods demonstrate compounds potent, broad-spectrum agents whose activity...
The problem of multidrug resistance in serious Gram-negative bacterial pathogens has escalated so severely that new cellular targets and pathways need to be exploited avoid many the preexisting antibiotic mechanisms are rapidly disseminating strains. discovery small-molecule inhibitors LpxC, enzyme responsible for first committed step biosynthesis lipid A, represents a clinically unprecedented strategy specifically act against organisms such as Pseudomonas aeruginosa members...
In this paper, we present the synthesis and SAR as well selectivity, pharmacokinetic, infection model data for representative analogues of a novel series potent antibacterial LpxC inhibitors represented by hydroxamic acid 1a.
The synthesis and biological activity of a new series LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members this have improved solubility free fraction when compared to compounds in the previously described biphenyl series, they maintain superior Gram-negative antibacterial comparator agents.
The development and optimization of a series quinolinylpurines as potent selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification 1 (AMG319), compound an IC50 16 nM in human whole blood assay (HWB), selectivity over large panel protein kinases, high level vivo efficacy measured by two rodent disease models inflammation.
Tyrosine kinase 2 (TYK2) is a member of the JAK family that regulates signal transduction downstream receptors for IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On basis human genetic emerging clinical data, selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering potentially differentiated profile compared currently approved inhibitors. The discovery ATP-competitive pyrazolopyrazinyl series inhibitors was...
Herein we describe the structure-aided design and synthesis of a series pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae Escherichia coli . Rat pharmacokinetic studies compound 17 demonstrate low clearance plasma protein binding. In addition, evidence is provided for number suggesting that siderophore receptors PiuA PirA play role drug uptake P. strain PAO1.
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through improved molecular understanding drug–target interactions combined with enhanced delivery these agents the site action. Herein we describe first application siderophore receptor-mediated drug uptake lactivicin analogues as a strategy that enables novel against clinically relevant bacteria. We...
Abstract Targeted protein degradation using heterobifunctional chimeras holds the potential to expand target space and grow druggable proteome. Most acutely, this provides an opportunity proteins that lack enzymatic activity or have otherwise proven intractable small molecule inhibition. Limiting potential, however, is remaining need develop a ligand for of interest. While number challenging been successfully targeted by covalent ligands, unless modification affects form function, it may...
The chemokines CCL3 and CCL5, as well their shared receptor CCR1, are believed to play a role in the pathogenesis of several inflammatory diseases including rheumatoid arthritis, multiple sclerosis, transplant rejection. In this study we describe pharmacological properties novel small molecular weight CCR1 antagonist, CP-481,715 (quinoxaline-2-carboxylic acid [4(R)-carbamoyl-1(S)-(3-fluorobenzyl)-2(S),7-dihydroxy-7-methyloctyl]amide). Radiolabeled binding studies indicate that binds human...
We report novel polymyxin analogues with improved antibacterial in vitro potency against resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell assay (hRPTEC) was used to inform structure-toxicity relationships further differentiate analogues. Replacement the Dab-3 residue Dap-3 combination relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as fatty acyl replacement yielded analogue 5x, which...