Taking a systems approach to the identification of novel therapeutic targets and biomarkers.

Systems biology focuses on the roles of cellular pathways and networks rather than single biomolecules to describe biological function. A systems view of biology requires technology that can generate and quantitatively analyze, large multi-dimensional data sets from many different sources. New technology has made this approach to drug discovery increasingly feasible. Detailed changes in cellular phenotype can be quantitatively measured using high content phenotypic screens. Changes in a cells entire transcriptome or proteome can be profiled in detail. Libraries of small molecules, peptides or poly-nucleotides such as siRNA can be screened to identify perturbagens that modulate transcriptomic, proteomic and cellular phenotypic signatures. These molecular agents can be used to deconvolute pathways and networks. The power of these technologies lies in their ability to generate complex biological data at massive scales. Integration and analysis of this multi-parametric data is vital to systems biology research. Patterns and relationships within these data sets can be revealed using factor and principal component analysis. These patterns can point to pathways that are relevant to specific biological processes making the ultimate goal of understanding the biology of a cell at the systems level possible.

Discovery of a small molecule antagonist of the parathyroid hormone receptor by using an N-terminal parathyroid hormone peptide probe.

Once-daily s.c. administration of either human parathyroid hormone (PTH)-(1-84) or recombinant human PTH-(1-34) provides for dramatic increases in bone mass in women with postmenopausal osteoporosis. We initiated a program to discover orally bioavailable small molecule equivalents of these peptides. A traditional high-throughput screening approach using cAMP activation of the PTH/PTH-related peptide receptor (PPR) as a readout failed to provide any lead compounds. Accordingly, we designed a new screen for this receptor that used a modified N-terminal fragment of PTH as a probe for small molecule binding to the transmembrane region of the PPR, driven by the assumption that the pharmacological properties (agonist/antagonist) of compounds that bound to this putative signaling domain of the PPR could be altered by chemical modification. We developed DPC-AJ1951, a 14 amino acid peptide that acts as a potent agonist of the PPR, and characterized its activity in ex vivo and in vivo assays of bone resorption. In addition, we studied its ability to initiate gene transcription by using microarray technology. Together, these experiments indicated that the highly modified 14 amino acid peptide induces qualitatively similar biological responses to those produced by PTH-(1-34), albeit with lower potency relative to the parent peptide. Encouraged by these data, we performed a screen of a small compound collection by using DPC-AJ1951 as the ligand. These studies led to the identification of the benzoxazepinone SW106, a previously unrecognized small molecule antagonist for the PPR. The binding of SW106 to the PPR was rationalized by using a homology receptor model.