Total synthesis of (+)-amphidinolide W and efforts toward total synthesis of (-)-lasonolide A.

Total synthesis of (+)-amphidinolide W and efforts toward total synthesis of (-)-lasonolide A

Discovery of a novel submicromolar inhibitor of the lymphoid specific tyrosine phosphatase

A series of small molecule inhibitors of the lymphoid specific tyrosine phosphatase were described. We report here a class of thiazolidine-2,4-diones and 2-thioxothiazolidin-4-ones as potent inhibitors of the lymphoid specific tyrosine phosphatase (Lyp) identified from high throughput screens. Chemical modification by incorporating the known phosphotyrosine (pTyr) mimics led to the discovery of a salicylate-based inhibitor with submicromolar potency

Potent Inhibitors of Huntingtin Protein Aggregation in a Cell-Based Assay

A quinazoline that decreases polyglutamine aggregate burden in a cell-based assay was identified from a high-throughput screen of a chemical-compound library, provided by the NIH Molecular Libraries Small Molecule Repository (MLSMR). A structure and activity study yielded leads with submicromolar potency

Discovery of novel small molecule cell type-specific enhancers of NF-κB nuclear translocation

A reported IKKβ inhibitor to inhibit NF-κB transcriptional activities in Jurkat T cells was found to enhance NF-κB translocation in HUVEC cells. These studies suggested a noncanonical NF-κB signaling independent to IKKβ in HUVEC cells. An IKKβ inhibitor reported to block NF-κB transcriptional activities in Jurkat T cells, was found to enhance NF-κB translocation in HUVEC cells. These studies suggested a noncanonical NF-κB signaling pathway independent of IKKβ in HUVEC cells

Inhibition of Lymphoid Tyrosine Phosphatase by Benzofuran Salicylic Acids

The lymphoid tyrosine phosphatase (Lyp, PTPN22) is a critical negative regulator of T cell antigen receptor (TCR) signaling. A single-nucleotide polymorphism (SNP) in the ptpn22 gene correlates with the incidence of various autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, and systemic lupus erythematosus. Since the disease-associated allele is a more potent inhibitor of TCR signaling, specific Lyp inhibitors may become valuable in treating autoimmunity. Using a structure-based approach, we synthesized a library of 34 compounds that inhibited Lyp with IC 50 values between 0.27 and 6.2 μM. A reporter assay was employed to screen for compounds that enhanced TCR signaling in cells, and several inhibitors displayed a dose-dependent, activating effect. Subsequent probing for Lyp's direct physiological targets by immunoblot analysis confirmed the ability of the compounds to inhibit Lyp in T cells. Selectivity profiling against closely related tyrosine phosphatases and in silico docking studies with the crystal structure of Lyp yielded valuable information for the design of Lyp-specific compounds

Discovery of potent non-urea inhibitors of soluble epoxide hydrolase

A class of potent non-urea inhibitors of soluble epoxide hydrolase was discovered via high throughput screening and SARs-guided modification. Soluble epoxide hydrolase (sEH) is a novel target for the treatment of hypertension and vascular inflammation. A new class of potent non-urea sEH inhibitors was identified via high throughput screening (HTS) and chemical modification. IC 50s of the most potent compounds range from micromolar to low nanomolar

Identification of N-(quinolin-8-yl)benzenesulfonamides as agents capable of down-regulating NFκB activity within two separate high-throughput screens of NFκB activation

We describe here a series of N-(quinolin-8-yl)benzenesulfonamides capable of suppressing the NFκB pathway identified from two high-throughput screens run at two centers of the NIH Molecular Libraries Initiative. These small molecules were confirmed in both primary and secondary assays of NFκB activation and expanded upon through analogue synthesis. The series exhibited potencies in the cell-based assays at as low as 0.6 μM, and several indications suggest that the targeted activity lies within a common region of the NFκB pathway