Welcome to SBS 2011 - SLAS

Gaylord Palms Resort and Convention Center | March 27–31, 2011 | Orlando, Florida, USA
Drug Repositioning: How it Fits with Current Drug Discovery Trends
Christopher A. Lipinski, Melior Discovery
Drug Repositioning (aka drug repurposing, indications discovery) is finding a new use for an existing drug. We now recognize
that 85–90 percent of single mechanism, target based knockouts are phenotypically silent because of network robustness.
The positive counterpart to this observation is that a drug that exhibits a robust phenotypic response in humans is by definition
modulating a sensitive network signaling pathway. In addition, it is invariably the case that an effective drug never has just a
single mechanism of action. This means that there is a rich reservoir of potentially useful new indications for existing drugs. In
many cases, we can discern a link to the originally described mechanism but sometimes a new beneficial effect is due to an
“off target” effect. Based on fundamental principles one can anticipate a parallel growth between drug repositioning and multi
targeted drug discovery, which is the deliberate search for drugs with multiple mechanisms.
Prodrugs: Regulatory and Clinical Development Requirements For Approval
Ken Phelps, Camargo Pharmaceutical Services, LLC
A prodrug of an existing or derailed pipeline drug product is an attractive way to improve drug safety or efficacy. The choice
of regulatory pathway, 505(b)(1) or 505(b)(2), will determine the cost and time to market approval. This choice is driven by the
characteristics of the prodrug, but mainly by where the prodrug cleaves to become the existing drug. Methods to determine
where this cleavage occurs and the resulting drug development program will be discussed and illustrated using case studies.
Exploring Ligand-Directed Functional Selectivity of GPCR With Bret-Based Biosensor Arrays
and Label-Free Impedance Measurements; Linking Signaling Signature to Drug Efficacy
Michel Bouvier, Drug Discovery Group, University of Montreal
Traditionally known for their ability to selectively activate a unique hetero-trimeric G protein, individual G protein-coupled
receptors (GPCR) have since been shown to activate multiple G protein subtypes as well as G-protein independent signaling
cascades. In addition, different ligands were found to selectively promote the engagement of distinct signaling partner
subsets of a given receptor. Some compounds were also found to have clearly distinct and some times opposite efficacies
toward different pathways engaged by the same receptor. This phenomenon—known as ligand-biased signaling or functional
selectivity--offers interesting opportunities to develop compounds with increased selectivity profiles but presents important
challenges for the drug discovery process, in particular in the context of high throughput screening. Since in many cases
the specific signaling pathway that should be targeted for optimal therapeutic activity is unknown, methods that would allow
monitoring multiple signaling pathways simultaneously would be great assets. We therefore developed new assays based on
luminescence and resonance energy transfer as well as label-free impedance measurements that allow monitoring multiple
signaling pathways and the ability to assess the structural determinants of ligand-biased signaling. Using these two types of
assays, we dissected the signaling cascades engaged by ligands that have biased efficacy toward various effectors, including
distinct G proteins, the adenylyl cyclase, the mitogen-activated protein kinase, Rho, ßarrestin and calcium pathways and
revealed distinct conformational rearrangements of the signaling modules involved. Combined with molecular modeling of
the recently solved 3D structures of the ßARs, these studies should provide the basis for the rational design of drugs with
predetermined biased signaling profiles and improved therapeutic activities.
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