This project includes the development of biochemical and target-focused assays based on specific protein or nucleic acid targets implicated in disease. The assay designs are considered in the context of analysis and progression strategies for evaluation of a wide range of compound classes using high throughput screening technologies. There is a strong emphasis on methods development research to advance assay and lead discovery efficiency. Complementing these activities we also explore and devise approaches for the interrogation of complex chemical libraries (e.g., natural product extracts, mRNA display). The work from this program is used to support a range of grant applications and prototype projects. The following are on-going: Radixin-mediated assembly of cAMP effectors. cAMP is a universal second messenger used by several hormones in every cell type. It is involved in multiple aspects of normal physiology and disease and thus a valid though challenging target for drug discovery. In collaboration with D. Altschuler (U. Pittsburgh) we are investigating assay strategies to specifically target a cAMP effector-scaffold complex involved in cAMP-dependent cell proliferation. Targeting protein palmitoylation with small molecules. In collaboration with A. Banerjee (NICHD, NIH) we are developing 1536-well compatible protein palmitoyl acyl transferase assays to evaluate chemical libraries for potential inhibitors of the enzyme as possible therapeutic leads for the large number of diseases to which this class of enzyme have been linked. These compounds are also anticipated to have value as structural, functional and pharmacological probes. Strategies for the discovery of small molecule ligands of RNA. In collaboration with Prof. N. Baird (U. Sciences) we are exploring assay designs to probe the interaction of small molecules with non-coding gene-regulatory mRNAs. The research has the potential of the discovery of novel antibiotics or anticancer agents. Assay development to enable discovery of novel small molecule antagonists of the receptor guanylate cyclase Npr1. In collaboration with M. Hoon (NIDCR, NIH) we are developing and testing novel assays of the b-type natriuretic peptide (BNP) receptor, Npr1. Recently the agonist, BNP was shown to be required for the transmission of itch sensation between peripheral and spinal cord nerves. The Npr1 assays will be used to identify antagonists for use in pharmacological treatments of chronic itch, a condition that results in long-term unremitting urge to scratch that significantly degrades the quality of life for sufferers. SIRPa-CD47 Protein-protein interaction. In collaboration with T. Miller (Paradigm Shift Therapeutics) and D. Roberts (NCI, NIH) our goal is to leverage the broad potential of CD47 as a molecular target in a number of tumors to create therapeutics that protect normal tissue from chemo and radiation therapy while differentially enhancing the effects of these therapies on the tumor. We are currently reengineering a medium throughput biochemical CD47 ligand binding assay to a higher throughput system capable of screening a larger number of molecules.
|Dahlin, Jayme L; Inglese, James; Walters, Michael A (2015) Mitigating risk in academic preclinical drug discovery. Nat Rev Drug Discov 14:279-94|
|Inglese, J (2014) Designing innovative therapies for neuropathic pain: pros and cons of target-based drug discovery. J Peripher Nerv Syst 19 Suppl 2:S6-9|
|Zhou, Ying; Asahara, Haruichi; Schneider, Nils et al. (2014) Engineering bacterial transcription regulation to create a synthetic in vitro two-hybrid system for protein interaction assays. J Am Chem Soc 136:14031-8|