Current Topics in Medicinal Chemistry - Volume 9, Issue 13, 2009

In 2005, the National Institutes of Heath (NIH) established the Molecular Libraries Screening Center Network (MLSCN). This initiative was a component of the NIH Roadmap for Medical Research [1], and hoped to build on the success of the Human Genome Project. In a simplistic analysis, if the human genome project addressed the question “what is the sequence of each protein in a human?”, the logical next question woul Read More

A variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads and to accelerate the development of drug candidates. The Emory Chemical and Biology Discovery Center (ECBDC) has been an active participant in the NIH's high-throughput screening (HTS) endeavor to identify potent small molecule probes for poorly studied proteins. Several of Emory's projects relate to cancer or viru Read More

Nuclear factor kappa B (NF-κB) is an important transcription factor. Aberrant regulation of the NF-κB pathway is frequently observed in a number of major ailments such as cancer and inflammatory diseases. Hence NF-κB modulators have been intensely pursued for their potential therapeutic applications. Numerous reviews have described recent progress in the development of these agents. More recently, a variety of structur Read More

The NIH Chemical Genomics Center (NCGC) was the inaugural center of the Molecular Libraries and Screening Center Network (MLSCN). Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for use in their research. We intend this review to serve as 1) an intr Read More

The Polo-like kinase (Plk) family comprises four cell cycle serine/threonine kinases, Plk1-4. Among these, Plk1 has been most thoroughly characterized; it contains a conserved kinase domain and a C-terminal docking site for S/T-phosphorylated proteins (polo-box domain, PBD). Polo-like kinases are deregulated in oncogenesis and therefore constitute a therapeutic target for cancer. A high throughput screening camp Read More

During the pilot phase of the NIH Molecular Library Screening Network, the Penn Center for Molecular Discovery focused on a series of projects aimed at high throughput screening and the development of probes of a variety of protease targets. This review provides our medicinal chemistry experience with two such targets - cathepsin B and cathepsin L. We describe our approach for hit validation, characterization and triage Read More

This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M1). An M1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M1 versus M4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to t Read More

Recent technological advances in flow cytometry provide a versatile platform for high throughput screening of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. Read More