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.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.

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.

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. IC50s of the most potent compounds range from micromolar to low nanomolar.A class of potent non-urea inhibitors of soluble epoxide hydrolase was discovered via high throughput screening and SARs-guided modification.

Vesicular monoamine transporter type 2 (VMAT2) is a newly emerging target for both diagnostic and therapeutic applications in diabetes mellitus. In pursuit of novel VMAT2 antagonists, we identified a potent hypoglycemic agent with a novel dihydropyridone scaffold. Several analogs were designed and synthesized. A preliminary structure activity relationship (SAR) showed that the dihydropyridone scaffold is required for the activity.A novel hypoglycemic dihydropyridone was serendipitously discovered in the course of synthesizing VMAT2 antagonists.

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.

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.A series of small molecule inhibitors of the lymphoid specific tyrosine phosphatase were described.

A new strategy in transition-state analog design is demonstrated to elicit catalytic antibodies. The strategy is based on substrate-assisted antibody catalysis and utilizes analogs designed to mimic the transition-state for intramolecular catalysis and thereby favor antibodies that can recruit catalytic groups from substrate. The hydrolysis of the benzoyl ester of cocaine provides an illustration. The benzoyl ester of cocaine is distant from the protonated nitrogen in the stable chair conformer but proximate in the strained boat form. An antibody stabilizing the boat form and approximating ester and amine could catalyze ester hydrolysis. To mimic the transition-state for the intramolecular catalysis, we synthesized a cocaine analog that replaces this ester with a methylenephenylphosphinate bridge to the tropane nitrogen. This bridged analog elicited 85 cocaine esterases out of 450 anti-analog antibodies–a performance markedly superior to that of a simple phosphonate ester-based analog with an identical tether. The correspondence of the analog to a “high energy” conformer eliminated product inhibition. For certain polyfunctional targets, substrate assistance can be an effective strategy for eliciting catalytic antibodies.

Cocaine covalently modifies proteins through a reaction in which the methyl ester of cocaine acylates the ɛ-amino group of lysine residues. This reaction is highly specific in vitro, because no other amino acid reacts with cocaine, and only cocaine's methyl ester reacts with the lysine side chain. Covalently modified proteins were present in the plasma of rats and human subjects chronically exposed to cocaine. Modified endogenous proteins are immunogenic, and specific antibodies were elicited in mouse and detected in the plasma of human subjects. Covalent modification of proteins could explain cocaine's autoimmune effects and provide a new biochemical approach to cocaine's long-term actions.