A5103080014- Cytokine Signaling Pathways and Interactions
- NF-κB Signaling Pathways
- Retinoids in leukemia and cellular processes
- Chronic Lymphocytic Leukemia Research
- Fatty Acid Research and Health
- Protease and Inhibitor Mechanisms
- Orthopedic Surgery and Rehabilitation
- Psoriasis: Treatment and Pathogenesis
- Lipid metabolism and biosynthesis
- Biochemical and Molecular Research
- T-cell and B-cell Immunology
- Receptor Mechanisms and Signaling
- Enzyme Structure and Function
- Asthma and respiratory diseases
- interferon and immune responses
- Inflammatory mediators and NSAID effects
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Synthesis and biological activity
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Bone health and treatments
- Osteoarthritis Treatment and Mechanisms
- Cell Adhesion Molecules Research
- Peroxisome Proliferator-Activated Receptors
Veterans Health Administration
2025
Toxicologie, Pharmacologie et Signalisation Cellulaire
2017
University of British Columbia
2016
Genentech
2012-2015
Hennepin County Medical Center
2009-2012
Pfizer (United States)
2009
University of Illinois Urbana-Champaign
2005
George Washington University
2003
University of Michigan
1996-1998
Combat Capabilities Development Command Soldier Center
1981
Resolving TYK2 locus genotype-to-phenotype differences reveals an immune signaling optimum that may be exploited therapeutically for treating autoimmune diseases.
Bruton's tyrosine kinase (Btk) is a nonreceptor cytoplasmic involved in B-cell and myeloid cell activation, downstream of Fcγ receptors, respectively. Preclinical studies have indicated that inhibition Btk activity might offer potential therapy autoimmune diseases such as rheumatoid arthritis systemic lupus erythematosus. Here we disclose the discovery preclinical characterization potent, selective, noncovalent inhibitor currently clinical development. GDC-0853 (29) suppresses B cell-...
Matrix metalloproteinase-13 (MMP13) is a Zn2+-dependent protease that catalyzes the cleavage of type II collagen, main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation osteoarthritis, making this an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with painful, joint-stiffening musculoskeletal side effect may be due to their lack selectivity. In our efforts develop disease-modifying osteoarthritis drug,...
The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown impressive clinical efficacy in a range of B-cell malignancies. However, acquired resistance emerged, and second generation therapies are now being sought. Ibrutinib is covalent, irreversible that modifies Cys481 the ATP binding site Btk renders enzyme inactive, thereby blocking receptor signal transduction. Not surprisingly, most commonly mutated residue cases to ibrutinib. Mutations at other sites, including Thr474,...
TYK2 is a JAK family protein tyrosine kinase activated in response to multiple cytokines, including type I IFNs, IL-6, IL-10, IL-12, and IL-23. Extensive studies of mice that lack expression indicate the IFN-α, IL-23 pathways, but not IL-6 or IL-10 are compromised. In contrast, there have been few role primary human cells. A genetic mutation at tyk2 locus results single patient has linked defects suggesting broad for cytokine responses. this article, we used panel novel potent small-molecule...
The kinase RIP1 acts in multiple signaling pathways to regulate inflammatory responses and it can trigger both apoptosis necroptosis. Its activity has been implicated a range of inflammatory, neurodegenerative, oncogenic diseases. Here, we explore the effect inhibiting genetically, using knock-in mice that express catalytically inactive D138N, or pharmacologically, murine-potent inhibitor GNE684. Inhibition reduced collagen antibody-induced arthritis, prevented skin inflammation caused by...
NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis systemic lupus erythematosus (SLE). Here, we show that experimental NZB/W F1 mice can be treated with a highly selective potent NIK small molecule inhibitor. Both vitro as well vivo, inhibition recapitulates pharmacological effects BAFF blockade, is clinically efficacious SLE. Furthermore, also affects T...
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...
Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with molecule 3. We used structure-based design discover 2,6-dichloro-4-cyanophenyl (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved potency JAK1 JAK2 selectivity relative Further eventually led compound 37 that showed good enzyme interleukin-12 (IL-12) cell potency, as well acceptable cellular excellent oral exposure in mice. When...
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting JAK1 pathway. Examination preferred binding conformation clinically effective, pan-JAK inhibitor 1 led to identification a novel, tricyclic hinge scaffold 3. Exploration SAR through series cycloamino and cycloalkylamino analogues demonstrated this template be highly tolerant substitution, with predisposition moderate selectivity isoform over JAK2. This...
A minor structural change to tertiary sulfonamide RORc ligands led distinct mechanisms of action. Co-crystal structures two compounds revealed mechanistically consistent protein conformational changes. Optimized phenylsulfonamides were identified as agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving in our biochemical assay also gave rise an increased production IL-17 human PBMCs whereas significant suppression under the same conditions. The most...
Systemic lupus erythematosus (SLE) is often associated with exaggerated B cell activation promoting plasma generation, immune-complex deposition in the kidney, renal infiltration of myeloid cells, and glomerular nephritis. Type-I IFNs amplify these autoimmune processes promote severe disease. Bruton's tyrosine kinase (Btk) inhibitors are considered novel therapies for SLE. We describe characterization a highly selective reversible Btk inhibitor, G-744. G-744 efficacious, superior to blocking...
Abstract The mechanism of the hardening body fats animals by dietary lipids which contain cyclopropene fatty acids has been studied. Dietary methyl sterculate increased stearic acid content egg yolk lipid and decreased activity desaturase system hen liver. were specific inhibitors livers since other acids, including two possible metabolites sterculic acid, failed to inhibit at equivalent concentrations. Sterculic was a more effective inhibitor than malvalic acid. Kinetic studies have shown...
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels selectivity for JAK1 over JAK2 to imidazopyrrolopyridine series inhibitors. X-ray structures analogue in complex with both and revealed differential ligand/protein interactions between two isoforms offered an explanation observed selectivity. Analysis historical data from related molecules was used develop set physicochemical compound design parameters impart desirable...
Retinoic acid receptor-related orphan receptor C (RORc, RORγ, or NR1F3) is a nuclear that plays major role in the production of interleukin (IL)-17. Considerable efforts have been directed toward discovery selective RORc inverse agonists as potential treatments inflammatory diseases such psoriasis and rheumatoid arthritis. Using previously reported tertiary sulfonamide 1 starting point, we engineered structural modifications significantly improved human rat metabolic stabilities while...
We report here structure-guided optimization of a novel series NF-κB inducing kinase (NIK) inhibitors. Starting from modestly potent, low molecular weight lead, activity was improved by designing type 11/2 binding mode that accessed back pocket past the methionine-471 gatekeeper. Divergent modes in NIK and PI3K were exploited to dampen inhibition while maintaining within these series. Potent compounds discovered selectively inhibit nuclear translocation NF-κB2 (p52/REL-B) but not canonical...
Membrane type (MT) matrix metalloproteinases (MMPs) are recently recognized members of the family Zn2+- and Ca2+-dependent MMPs. To investigate proteolytic capabilities human MT4-MMP (i.e. MMP-17), we have cloned DNA encoding its catalytic domain (CD) from a breast carcinoma cDNA library. Human membrane 4 MMP CD (MT4-MMPCD) protein, expressed as inclusion bodies inEscherichia coli, was purified to homogeneity refolded in presence Zn2+ Ca2+. While MT4-MMPCD cleaved synthetic substrates...
Herein we report the discovery of C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent orally bioavailable JAK1 inhibitors with selectivity over JAK2. The inhibitor 4 exhibited not only improved potency relative unsubstituted compound 3 but also notable vs JAK2 (20-fold >33-fold in biochemical cell-based assays, respectively). Features X-ray structures complex both are delineated. Efforts improve vitro vivo ADME properties while maintaining described,...