A5087662158- Hepatitis C virus research
- Fluorine in Organic Chemistry
- Bacterial biofilms and quorum sensing
- Chemical Synthesis and Analysis
- Antibiotic Resistance in Bacteria
- Pancreatic function and diabetes
- Cancer therapeutics and mechanisms
- HIV/AIDS drug development and treatment
- Hepatitis B Virus Studies
- Lipid metabolism and biosynthesis
- Endoplasmic Reticulum Stress and Disease
- Fungal Plant Pathogen Control
- Synthesis and Catalytic Reactions
- Biochemical and Molecular Research
- Tuberculosis Research and Epidemiology
- Synthesis and Characterization of Heterocyclic Compounds
- Computational Drug Discovery Methods
- Carbohydrate Chemistry and Synthesis
- Mycobacterium research and diagnosis
- Cell death mechanisms and regulation
- Bacterial Genetics and Biotechnology
- Melanoma and MAPK Pathways
- Acute Myeloid Leukemia Research
- Synthesis of heterocyclic compounds
- Plant chemical constituents analysis
Center Point
2024
Broad Institute
2013-2024
Harvard University
2024
Massachusetts Institute of Technology
2024
Novartis (United States)
2007-2020
Novartis (Switzerland)
2015
Bristol-Myers Squibb (United States)
2001-2013
Weatherford College
2007
ABSTRACT Using a cell-based replicon screen, we identified class of compounds with thiazolidinone core structure as inhibitors hepatitis C virus (HCV) replication. The concentration one such compound, BMS-824, that resulted in 50% inhibition HCV replication was ∼5 nM, therapeutic index >10,000. compound showed good specificity for HCV, it not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, mutations identified. A combination amino acid...
The MCL1 gene is frequently amplified in cancer and codes for the antiapoptotic protein myeloid cell leukemia 1 (MCL1), which confers resistance to current standard of care. Therefore, an attractive anticancer target. Here we describe BRD-810 as a potent selective inhibitor its key design principle rapid systemic clearance potentially minimize area under curve-driven toxicities associated with inhibition. induced killing within 4 h vitro but, same 4-h window, had no impact on viability or...
The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in genotype 1b replicon assay via high-throughput screening campaign. A more potent analogue, BMS-824 (18), used resistance mapping studies, which revealed that inhibitory activity related to disrupting the function nonstructural protein 5A. Despite development coherent and interpretable SAR, it subsequently discovered DMSO 18 underwent an oxidation structural rearrangement afford thiohydantoin 47,...
The outer membrane of Gram-negative bacteria is a formidable permeability barrier which allows only small subset chemical matter to penetrate. This can hinder the study cellular processes and compound mechanism action, as many compounds including antibiotics are precluded from entry despite having intracellular targets. Consequently, permeabilizing invaluable tools in such studies. Many existing known perturb also impact inner integrity, polymyxins their derivatives, making these probes...
The alternative pathway (AP) of the complement system is a key contributor to pathogenesis several human diseases including age-related macular degeneration, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and various glomerular diseases. serine protease factor B (FB) node in AP integral formation C3 C5 convertase. Despite prominent role FB AP, selective orally bioavailable inhibitors, beyond our own efforts, have not been reported previously. Herein we...
ABSTRACT The exceptional in vitro potency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into an vivo effect proof-of-concept clinical trials. Although 50% effective concentration (EC 50 ) initial lead, thiazolidinone BMS-824, was ∼10 nM replicon assay, it underwent transformation to other inhibitory species after incubation cell culture medium. biological profile including EC , drug required reduce growth by (CC ), and resistance profile, however, remained...
The difficulty in treating Gram-negative bacteria can largely be attributed to their highly impermeable outer membrane (OM), which serves as a barrier many otherwise active antibiotics. This overcome with the use of perturbant molecules, disrupt OM integrity and sensitize clinically available Gram-positive-active Although new perturbants have been identified recent years, most these molecules are impeded by toxicity due similarities between pathogen host cell membranes. For example, our...
Crystallization of a maltose-binding protein MCL1 fusion has yielded robust crystallography platform that generated the first apo crystal structure, as well five ligand-bound structures. The ability to obtain fragment-bound structures advances structure-based drug design efforts that, despite considerable effort, had previously been intractable by crystallography. In ligand-independent form we identify inhibitor binding modes not observed in earlier crystallographic systems. This MBP-MCL1...
A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and 1b (G-1b) replicon inhibition selectivity against BVDV cytotoxicity. SAR emerging an examination prolinamide cap region revealed 11 be a selective NS5A inhibitor exhibiting submicromolar potency both G-1a G-1b replicons. Additional structural refinements resulted in identification 30 as potent, dual G-1a/1b inhibitor.
The prevalence of obesity-induced type 2 diabetes (T2D) is increasing worldwide, and new treatment strategies are needed. We recently discovered that obesity activates a previously unknown pathway promotes both excessive hepatic glucose production (HGP) defective insulin signaling in hepatocytes, leading to exacerbation hyperglycemia resistance obesity. At the hub this kinase cascade involving calcium/calmodulin-dependent protein II (CaMKII), p38α mitogen-activated (MAPK), MAPKAPK2/3...
SUMMARY The surge of antimicrobial resistance threatens efficacy current antibiotics, particularly against Pseudomonas aeruginosa , a highly resistant gram-negative pathogen. asymmetric outer membrane (OM) P. combined with its array efflux pumps provide barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT 1 target-based, whole-cell screening strategy, discover small molecule probes that kill mutants depleted for essential proteins localized at...
High DGAT1 expression levels in the small intestine highlight critical role this enzyme plays nutrient absorption. Identification of inhibitors which predominantly inhibit gut is an attractive drug discovery strategy with anticipated benefits reduced systemic toxicity. In report we describe our and optimization whose plasma exposure minimized by action transporters, including P-glycoprotein transporter. The impact unique absorption profile on efficacy rat dog models presented.
A direct binding screen of 100 000 sp3-rich molecules identified a single diastereomer macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). comprehensive toolbox biophysical methods was applied validate the original hit and subsequent analogues also established mode competitive with NOXA BH3 peptide. X-ray crystallography ligand bound MCL1 reveals remarkable ligand/protein shape complementarity diverges from previously disclosed inhibitor costructures.
Modification of a gut restricted class benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes include bioisosteric replacement the amide oxadiazole and α,α-dimethylation carboxylic acid, improving potency permeability. Since is expressed in small intestine, both can suppress postprandial triglycerides during acute lipid challenges rats dogs. Interestingly, only was found be effective suppressing body weight gain relative control diet-induced obese...