Sinha laboratory focuses on development and optimization of brain permeable lead compounds as tool candidates and therapies for Neurodegenerative diseases, including Alzheimer’s disease (AD). Sinha lab also specializes in developing prodrug approaches to improve the selectivity and accessibility to the brain. Beyond amyloid hypothesis, human genetics and mechanistic studies revealed exciting disease-associated target proteins that remain largely unexplored. Working with other labs at Appel Institute, Sinha laboratory aims to identify and develop hit to lead candidates for some of these target proteins restoring function in microglia, astroglia, and synaptic function. Hit candidates will be identified by classical and virtual high throughput screening (HTS) assays, and Medicinal Chemistry is performed for the lead discovery.
1) Developed and evaluated chemically programmed antibody strategy, antibody-drug conjugates and prodrugs of anticancer agents that improve pharmacokinetic properties and selectivity of small molecules. These studies were funded through NCI.
2) Developed antibody-catalyzed reactions and prepared numerous naturally occurring compounds, including acetogenins and epothilones. Acetogenins are potent Complex I inhibitors and epothilones are anticancer agents.
3) Prepared and examined Gleevec and DV2-103 analogs that potently inhibit Amyloid-b (Ab) production in cell culture and works synergistically when combined with a b secretase inhibitor. In addition, natural product extracts were screened to identify a g secretase inhibitor, and brain-permeable amide prodrugs of the FDA approved Transthyretin stabilizer, Tafamidis, were developed to target and stabilize the protein in brain. These studies were funded through the JPB foundation.
4) Inhibitors of CK1 autophosphorylation were developed to selectively increase PS1-Ser367 phosphorylation that was earlier shown to reduce Ab load in brain through inducing autophagy. These studies were funded through the JPB foundation and Cure Alzheimer’s fund.