A5047829660- Hepatitis C virus research
- Chemical Synthesis and Analysis
- Quinazolinone synthesis and applications
- HIV/AIDS drug development and treatment
- Synthesis and biological activity
- Protein Kinase Regulation and GTPase Signaling
- Click Chemistry and Applications
- Melanoma and MAPK Pathways
- Cancer Mechanisms and Therapy
- Cancer-related gene regulation
- Monoclonal and Polyclonal Antibodies Research
- Cancer therapeutics and mechanisms
- Biochemical and Molecular Research
- Synthesis and Characterization of Heterocyclic Compounds
- Radical Photochemical Reactions
- Synthesis and Biological Evaluation
- Synthesis of Organic Compounds
- Cytokine Signaling Pathways and Interactions
- Hepatitis B Virus Studies
- RNA modifications and cancer
- Traditional and Medicinal Uses of Annonaceae
- Bioactive natural compounds
- Chromatin Remodeling and Cancer
- Neurogenetic and Muscular Disorders Research
- Synthesis of Indole Derivatives
AstraZeneca (Brazil)
2025
Medicina
2025
AstraZeneca (United States)
2020-2024
Pfizer (United States)
2011-2020
Pearl River Community College
2000-2010
Princeton University
2004
Indian Institute of Technology Madras
1988-2002
University at Buffalo, State University of New York
1990-1994
This work describes the first rational targeting of tyrosine residues in a protein binding site by small-molecule covalent probes. Specific active mRNA-decapping scavenger enzyme DcpS were modified using reactive sulfonyl fluoride inhibitors. Structure-based molecular design was used to create an alkyne-tagged probe bearing warhead, thus enabling efficient capture from complex proteome. Use competition experiments with diaminoquinazoline inhibitor permitted quantification intracellular...
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,...
Irreversible enzyme inhibitors and covalent chemical biology probes often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (e.g., acrylamide) on ligand template. However, residues are not always available for site-specific labeling, therefore new approaches needed to expand toolkit appropriate electrophiles ("warheads") that target alternative amino acids. We previously described rational targeting tyrosine in active site (the mRNA decapping...
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery compound 16, highly potent and selective inhibitor that active in replicon system.
Heat shock protein 90 (Hsp90) is a molecular chaperone that responsible for activating many signaling proteins and promising target in tumor biology. We have identified small-molecule benzisoxazole derivatives as Hsp90 inhibitors. Crystallographic studies show these compounds bind the ATP binding pocket interacting with Asp93. Structure based optimization led to identification of potent analogues, such 13, good biochemical profiles.
Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule antagonists have yet progressed into clinical trials. Investigation series linear peptide ligands to characterization their binding site has enabled the design novel macrocyclic are themselves potent antagonists.
Sickle cell disease (SCD) is a genetic disorder caused by single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled (HbS). In deoxygenated state, polymerization HbS leads to sickling red blood cells (RBC). Several downstream consequences and RBC include vaso-occlusion, hemolytic anemia, stroke. We report design noncovalent modulator HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered virtual screening confirmed through...
With high-throughput screening, substituted dibenzo[c,f][2,7]naphthyridine 1 was identified as a novel potent and selective phosphoinositide-dependent kinase-1 (PDK-1) inhibitor. Various regions of the lead molecule were explored to understand SAR requirement for this scaffold. The crystal structure with kinase domain PDK-1 confirmed binding in active site. key interaction site residues, observed SAR, biological profile are discussed detail.
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure complex confirmed binding near active site region. optimization approach SAR are discussed detail.
Inhibitor of secreted frizzled related protein-1 (sFRP-1) would be a novel potential osteogenic agent, since loss sFRP-1 affects osteoblast proliferation, differentiation, and activity, resulting in improved bone mineral density, quality, strength. We have identified small molecule diarylsulfone sulfonamide derivatives as inhibitors. Structure-activity relationship generated for various regions the scaffold was utilized to improve biochemical profile, identification potent selective...
A new solid-phase synthesis of various substituted 2-amino-4(1H)-quinazolinones from a resin bound amine component is described. The was readily converted to the corresponding polymer S-methylthiopseudourea. Condensation with different isatoic anhydrides afforded 2-amino-4(1H)-quinazolinone derivatives. method amenable for combinatorial library generation.
ABSTRACT A novel nonnucleoside inhibitor of hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp), [(1 R )-5-cyano-8-methyl-1-propyl-1,3,4,9-tetrahydropyano[3,4-b]indol-1-yl] acetic acid (HCV-371), was discovered through high-throughput screening followed by chemical optimization. HCV-371 displayed broad inhibitory activities against the NS5B RdRp enzyme, with 50% concentrations ranging from 0.3 to 1.8 μM for 90% isolates derived HCV genotypes 1a, 1b, and 3a. showed no activity a panel...