A5044341935- Melanoma and MAPK Pathways
- Computational Drug Discovery Methods
- Synthesis and biological activity
- SARS-CoV-2 and COVID-19 Research
- PI3K/AKT/mTOR signaling in cancer
- Cytokine Signaling Pathways and Interactions
- Carbohydrate Chemistry and Synthesis
- Enzyme Catalysis and Immobilization
- Neuropeptides and Animal Physiology
- Cell Image Analysis Techniques
- Pharmacological Receptor Mechanisms and Effects
- Colorectal Cancer Treatments and Studies
- Quinazolinone synthesis and applications
- Tryptophan and brain disorders
- Diet and metabolism studies
- Chronic Myeloid Leukemia Treatments
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Hepatitis C virus research
- 14-3-3 protein interactions
- Pancreatic function and diabetes
- Schizophrenia research and treatment
- Cancer Mechanisms and Therapy
- scientometrics and bibliometrics research
- Angiogenesis and VEGF in Cancer
- RNA and protein synthesis mechanisms
Harvard University
2021-2022
Boston VA Research Institute
2021-2022
Alkermes (United States)
2015-2022
Alkermes (Ireland)
2018-2021
University of Rochester
2018
Vertex Pharmaceuticals (United States)
2003-2017
Tufts Medical Center
2004-2005
Molecular Oncology (United States)
2005
Tufts University
2004-2005
Saarland University
2005
Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, majority patients develop resistance disease progression after approximately 12 months. Reactivation ERK a common driver this setting. Here we report discovery BVD-523 (ulixertinib), novel, reversible, ATP-competitive ERK1/2...
(<i>S</i>)-1-((<i>S</i>)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2<i>R</i>,3<i>S</i>)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (<i>S</i>)-3-({1-[(<i>S</i>)-1-((<i>S</i>)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2yl]-methanoyl}-amino)-4-oxo-butyric (VRT-043198), a potent and selective inhibitor interleukin-converting enzyme/caspase-1 subfamily...
The smaller form of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in two human diseases that affect its principal sites expression. Thus, destruction pancreatic beta cells, which results insulin-dependent diabetes mellitus (IDDM), and impairment GABA-ergic synaptic transmission Stiff-Man syndrome (SMS) are both characterized by circulating autoantibodies to GAD65. Anti-GAD65 IDDM predominantly directed conformational epitopes. Here we report...
The Ras/Raf/MEK/ERK signal transduction, an oncogenic pathway implicated in a variety of human cancers, is key target anticancer drug design. A novel series pyrimidylpyrrole ERK inhibitors has been identified. Discovery conformational change for lead compound 2, when bound to ERK2 relative antitarget GSK3, enabled structure-guided selectivity optimization, which led the discovery 11e, potent, selective, and orally bioavailable inhibitor ERK.
The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points viral life cycle could help tackle current, as well future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale silico screening platform, VirtualFlow, search inhibitors that target...
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro conserved among coronaviruses and distinct from human proteases. Viral replication depends on cleavage viral polyprotein at multiple sites. We present crystal structures SARS-CoV-2 bound to two substrate peptides. show how recognizes substrates subtle changes in accommodation can drive large catalytic efficiency. One...
A series of monosubstituted deoxy and deoxyfluoro 2,4-dinitrophenyl (DNP) β-d-glycopyranosides was synthesized used to probe the mechanism spontaneous β-glycoside hydrolysis. Their relative rates hydrolysis followed order 2-deoxy > 4-deoxy 3-deoxy ≈ 6-deoxy parent 6-deoxy-6-fluoro 3-deoxy-3-fluoro 4-deoxy-4-fluoro 2-deoxy-2-fluoro. Hammett correlations pH-independent each 6-, 4-, 3-, 2-position substituted glycosides with σI value for sugar ring substituent were linear (r = 0.95 0.999, ρI...
The role of noncovalent interactions in the catalytic mechanism Agrobacterium faecalis beta-glucosidase was investigated by steady-state and pre-steady state kinetic analysis hydrolysis a series monosubstituted aryl glycosides, which hydroxyl groups on glycone were substituted hydrogen or fluorine. Contributions each group to binding these substrates at ground are relatively weak (interaction energies 3.3 kJ/mol smaller) but much greater two transition states (glycosylation deglycosylation)....
Akt is a central regulator of cardiomyocyte survival after ischemic injury in vitro and vivo, but the mechanisms regulating activity postischemic are not known. Furthermore, although much known about detrimental role that c-Jun N-terminal kinases (JNKs) play promoting death cells exposed to various stresses, little molecular by which JNK activation can be protective. We report JNKs necessary for reactivation injury. identified Thr450 as residue phosphorylated JNKs, phosphorylation status...
The Ras/Raf/MEK/ERK signal transduction is a key oncogenic pathway implicated in variety of human cancers. We have identified novel series pyrazolylpyrroles as inhibitors ERK. Aided by the discovery two distinct binding modes for pyrazolylpyrrole scaffold, structure-guided optimization culminated 6p, potent and selective inhibitor
While several therapeutic options exist, the need for more effective, safe, and convenient treatment a variety of autoimmune diseases persists. Targeting Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses can contribute to aberrant immune function associated with disease, has emerged as novel attractive approach development new disease therapies. We screened our compound library against JAK3, key kinase cells, identified multiple scaffolds showing good...
Telaprevir 2 (VX-950), an inhibitor of the hepatitis C virus (HCVa) NS3-4A protease, is in phase 3 clinical trials. One major metabolites its P1-(R)-diastereoisomer, (VRT-394), containing inversion at chiral center next to α-ketoamide on exchange a proton with solvent. Compound approximately 30-fold less active against HCV protease. In attempt suppress epimerization without losing activity that site was replaced deuterium (d). The compound 1 (d-telaprevir) as efficacious vitro inhibition...
A combination of buprenorphine (BUP) and samidorphan (SAM) at a 1:1 (mg/mg) fixed-ratio dose is being investigated as an adjunctive treatment major depressive disorder (BUP/SAM, ALKS 5461). Both [<sup>3</sup>H]BUP [<sup>3</sup>H]SAM bound to the <i>μ</i>-, <i>κ</i>-, <i>δ</i>-opioid receptors (MOR, KOR, DOR, respectively) with K<sub>d</sub> values 3 nM or less. dissociated from MOR more slowly than did. In [<sup>35</sup>S]GTP<i>γ</i>S assay, BUP was partial agonist MOR, DOR. SAM antagonist...
GAD65, the smaller isoform of γ-aminobutyric acid-synthesizing enzyme glutamic acid decarboxylase is detected as an α/β doublet distinct mobility on SDS-polyacrylamide gel electrophoresis. Glutamic (GAD) 65 reversibly anchored to membrane synaptic vesicles in neurons and synaptic-like microvesicles pancreatic β-cells. Here we demonstrate that GAD65α but not β phosphorylated vivo vitro several cell types. Phosphorylation cause heterogeneity represents a unique post-translational modification...
The synthesis and characterization of a novel polycyclic azaindole based derivative is disclosed, its binding to JAK2 described. compound further evaluated for ability block the EPO/JAK2 signaling cascade in vitro vivo.
Background: Olanzapine, regarded as one of the most efficacious antipsychotic medications for treatment schizophrenia, is associated with a high risk weight gain and metabolic dysfunction. ALKS 3831, clinical candidate combination olanzapine samidorphan, an opioid receptor antagonist. The addition samidorphan intended to mitigate dysregulation use olanzapine. Methods: Non-clinical studies were conducted assess effects alone in at clinically relevant exposure levels. Results: Chronic...
The COVID-19 pandemic has generated an unprecedented response within the scientific community. Extraordinary efforts have been undertaken to identify potential new therapeutics treat SARS-CoV-2 infection spanning traditional medicinal chemistry, repurposing, and computational approaches. breadth of effort rapid progression many small molecules clinical testing provide opportunity determine what chemical approaches most efficient in identifying treatments how this may inform preparation for...
The beta-glucosidase from Agrobacterium sp. catalyzes the hydrolysis of beta-glucosides via a covalent alpha-D-glucopyranosyl-enzyme intermediate involving Glu358. Hydrolysis 2,4-dinitrophenyl beta-D-glucopyranoside by low activity Glu358Asp mutant is accompanied time-dependent inactivation enzyme. Through kinetic studies, labeling, and sequence analysis, shown to be consequence occasional (1 time in 1100) attack Tyr298 on anomeric center substrate, place catalytic nucleophile, with...
Abstract We report the design, chemical synthesis, and structural functional characterization of a novel reagent for protein sequence analysis by Edman degradation, yielding amino acid derivatives rapidly detectable at high sensitivity ion‐evaporation mass spectrometry. demonstrate that 3‐[4′(ethylene‐ N, N ‐trimethylamino)phenyl]‐2‐isothiocyanate is chemically stable shows coupling cyclization/cleavage yields comparable to phenylisothiocyanate, standard in analysis, under conditions...