The high cost associated with developing new chemical entities (NCEs) creates a clear demand for better prediction of toxicity and efficacy to thus enable more effective SAR early in the discovery process. The primary causes of compound attrition are poor pharmacokinetics, lack of efficacy, and off-target toxicity.
Compound performance in these areas is often not adequately addressed until pre-clinical development, at which point failures are quite costly. The implementation of more physiologically relevant models and assays earlier in the discovery and development pipeline could reduce the overall cost of drug development and potentially diminish market withdrawal.
Several platforms exist for precise, high-throughput interrogation of biological responses in cellular models. However, current in vitro models used on these platforms typically include immortalized cell lines, human cadaveric tissue, or primary cultures of nonhuman animal origin.
Each of these cellular models presents limitations that contribute to the overall low predictability of in vivo effects, including limited biological relevance of immortalized cell lines, functional variability of primary cell cultures, and/or the low throughput of assays based on isolated tissues.
Terminal cell types differentiated from human embryonic or induced pluripotent stem cells (ESCs or iPSCs, respectively) have emerged as a valuable alterative to current cell-based models. The indefinite self-renewing capacity of iPSCs provides an inexhaustible supply of consistent starting material.
Highly structured differentiation protocols followed by rigorous quality control procedures ensure a highly reproducible cellular model. Additionally, the industrial-scale production of cellular models and their intrinsic relevant human biology make stem cell-derived cell types suitable for high-throughput screening in drug discovery.