METHODS FOR IDENTIFYING PHARMACOLOGY AND TOXICOLOGY

摘要

The invention combines a microaπray and cell-based screening strategy that enables rapid identification of possible mechanisms underpinning the pharmacology and toxicology of drug candidates. The methods of the invention identified unique properties relating to apoptosis and the anti-inflammatory response elicited by several peroxisome proliferator activated receptor gamma (PPARϜ) ligands. The methods illustrate, for example, that PPARϜ ligands that are safe and effective drugs {e.g., Actos, Avandia) either do not induce apoptosis or only modestly induce apoptosis. Conversely, PPARϜ ligands that have failed clinical development (e.g., Ciglitazonc; Day, C, Diabet. Med., 16: 179-192 (1999)) or that have been withdrawn from the market (e.g., Troglitazone (Rezulin)) due to hepatotoxicity are potent inducers of apoptosis. The methods of the invention also illustrate that suppression of gene expression and protein expression for several pro-inflammatory factors by some PPARϜ ligands occurs as a consequence of apoptotic induction (i.e., apoptosis produces an anti-inflammatory response). The invention also provides biomarkers for cellular pathways and methods for stratifying patient groups according to their biomarker expression as well as biomarkers that discriminate safe and effective drugs from compounds that have acute toxicities. These biomarkers provide novel insights into the mechanism of action and toxicity for test compounds, including cell death, anti-inflammatory activity, hepatotoxicity, and carcinogenicity. The methods arc highly scalable and have broad application from discovery to the clinic, including compound prioritization, predictive pharmacology and toxicology; mechanism of action studies; and prognostic and diagnostic biomarker discovery.