A5050073024- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Amino Acid Enzymes and Metabolism
- RNA modifications and cancer
- Receptor Mechanisms and Signaling
- Ion Channels and Receptors
- Ion channel regulation and function
- Asthma and respiratory diseases
- Cardiac electrophysiology and arrhythmias
- Monoclonal and Polyclonal Antibodies Research
- Phytochemicals and Antioxidant Activities
- Cancer-related Molecular Pathways
- Fatty Acid Research and Health
- Pancreatic and Hepatic Oncology Research
- Immune Cell Function and Interaction
- Postharvest Quality and Shelf Life Management
- T-cell and B-cell Immunology
- Viral Infectious Diseases and Gene Expression in Insects
- Neuroscience and Neural Engineering
- Bioactive Compounds and Antitumor Agents
- Pharmacological Receptor Mechanisms and Effects
- 3D Printing in Biomedical Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Cell Adhesion Molecules Research
- Muscle activation and electromyography studies
Roche (United States)
2017
Calithera (United States)
2013-2014
The University of Texas MD Anderson Cancer Center
2014
Affymax (United States)
1995-1997
University of California, San Francisco
1986-1993
University of California San Francisco Medical Center
1986
Howard Hughes Medical Institute
1986
Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 a potent, selective, orally bioavailable inhibitor both splice variants glutaminase (KGA GAC). had antiproliferative activity triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with marked decrease consumption, production, oxygen steady-state levels...
Despite the development of effective therapies, a substantial proportion asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, rodents, TRPA1 is involved induction airway inflammation hyperreactivity. Here, discovery early clinical GDC-0334, highly potent, selective, orally bioavailable antagonist, described. GDC-0334 inhibited function on smooth...
Transient receptor potential ankyrin 1 (TRPA1) is a nonselective calcium ion channel highly expressed in the primary sensory neurons, functioning as polymodal sensor for exogenous and endogenous stimuli, has been implicated neuropathic pain respiratory disease. Herein, we describe optimization of potent, selective, orally bioavailable TRPA1 small molecule antagonists with strong vivo target engagement rodent models. Several lead molecules preclinical single- short-term repeat-dose toxicity...
Gabapentin is thought to be absorbed from the intestine of humans and animals by a low-capacity solute transporter localized in upper small intestine. Saturation this at doses used clinically leads dose-dependent pharmacokinetics high interpatient variability, potentially resulting suboptimal drug exposure some patients. XP13512 [(+/-)-1-([(alpha-isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane acetic acid] novel prodrug gabapentin designed throughout high-capacity nutrient...
Ion channels regulate a variety of physiological processes and represent an important class drug target. Among the many methods studying ion channel function, patch clamp electrophysiology is considered gold standard by providing ultimate precision flexibility. However, its utility in discovery impeded low throughput. Additionally, characterization endogenous primary cells remains technical challenging. In recent years, automated (APC) platforms have been developed to overcome these...
The tetradecapeptide somatostatin (SOM 14) and a 28-amino acid biosynthetic precursor 28) are constituents of diverse neuroendocrine tissues that released by noxious stimuli from subset sensory nerve endings, substantially modify the functions basophils mast cells. SOM-like factors were detected initially in fluid phase suspensions immunologically challenged rat basophilic leukemia cells (RBL), purified ethanol/0.2 M acetic (3/1, v/v) extracts replicate portions 3 X 10(9) RBL. Sephadex G-25...
Significance Subtype-selective modulation of ion channels is often important, but extremely difficult to achieve for drug development. Using Nav1.7 as an example, we show that this challenge could be attributed poor design in channel assays, which fail detect most potent and selective compounds are biased toward nonselective mechanisms. By exploiting different binding sites modes gating, successfully direct a membrane potential assay non–pore-blocking mechanisms identify Nav1.7-selective...
Using structure- and ligand-based design principles, a novel series of piperidyl chromane arylsulfonamide Nav1.7 inhibitors was discovered. Early optimization focused on improvement potency through refinement the low energy ligand conformation mitigation high in vivo clearance. An vitro hepatotoxicity hazard identified resolved lipophilicity lipophilic efficiency to arrive at GNE-616 (24), highly potent, metabolically stable, subtype selective inhibitor Nav1.7. Compound 24 showed robust...
The transient receptor potential ankyrin 1 (TRPA1) channel functions as an irritant sensor and is a therapeutic target for treating pain, itch, respiratory diseases. As ligand-gated channel, TRPA1 can be activated by electrophilic compounds such allyl isothiocyanate (AITC) through covalent modification or noncovalent agonists ligand binding. However, how leads to opening and, importantly, binding activates are not well-understood. Here we report class of piperidine carboxamides (PIPCs)...
Studies on the binding of IL-2 to its receptor (IL-2R) have generally been limited receptors expressed cell surfaces. This has hampered detailed kinetic and mechanistic studies at molecular level. We prepared soluble extracellular domains all three subunits (called α, β γ) by recombinant techniques used these perform their properties using technique surface plasmon resonance. describe a novel approach whereby are assembled an antibody surface, being held epitope engineered into C-terminus...
Sequences encoding the transmembrane domain of Rous sarcoma virus envelope (Env) glycoprotein were deleted and replaced with sequences that signal addition a glycosyl phosphatidylinositol (GPI) membrane anchor. Stable NIH 3T3 cell lines expressing either wild-type transmembrane-anchored Env or chimera GPI tail established. The GPI-anchored is expressed, oligomerized, transported to surface in manner identical its counterpart. GPI-linked protein quantitatively removed from by treatment...
Rabbit anti-idiotypic IgG antibodies to the combining site of a mouse monoclonal IgG2b antibody leukotriene B4 (LTB4) cross-reacted with human polymorphonuclear (PMN) leukocyte receptors for LTB4. Anti-idiotypic and Fab both inhibited binding [3H]LTB4, but not [3H]N-formylmethionyl-leucylphenylalanine (fMLP), PMN leukocytes similar concentration-effect relationships, whereas neither nonimmune rabbit nor had any inhibitory activity. At concentration that by 50% [3H] LTB4 leukocytes,...
Abstract Glutamine is required for the growth of a broad range tumor cells. An important step in metabolism glutamine its conversion to glutamate, which catalyzed by mitochondrial enzyme glutaminase. GLS, form expressed most cells, up-regulated sub-set glutamine-requiring Suppression GLS genetic knockdown or with small molecule inhibitors slows these To further evaluate as an oncology therapeutic target, we have developed series novel and potent that are orally bioavailable, permitting both...
Abstract Many tumor cells are dependent on glutamine (Gln) and Gln-derived metabolites to meet bioenergetic biosynthetic demands. A key cellular reaction in the utilization of Gln is its deamidation by enzyme glutaminase yield glutamate (Glu). We have developed a series potent selective small molecule inhibitors for evaluation as novel cancer therapeutics. These exhibit 5-20 nM potency against broadly-expressed form (GLS) with minimal activity liver (GLS2). Expression analysis (see below)...
<p>PDF - 85K, Supplementary Figure S5. Induction of apoptotic cell death by CB-839.</p>
<p>PDF - 246K, Supplementary Materials and Methods.</p>
<p>PDF - 126K, Supplementary Figure S3. TNBC primary tumors and cell lines have elevated glutaminase (GAC) mRNA levels.</p>
<p>PDF - 189K, Supplementary Figure S2. CB-839 has potent anti-proliferative activity in TNBC cells that is associated with selective impairment of glutamine utilization.</p>
<p>PDF - 125K, Supplementary Figure S4. Markers of glutamine utilization are increased in TNBC cell lines relative to receptor-positive lines.</p>