Small Molecule Screening in Human Induced Pluripotent Stem Cell-derived Terminal Cell Types

Sandra J Engle,Fabien Vincent

doi:10.1074/jbc.r113.529156

Abstract

A need for better clinical outcomes has heightened interest in the use of physiologically relevant human cells in the drug discovery process. Patient-specific human induced pluripotent stem cells may offer a relevant, robust, scalable, and cost-effective model of human disease physiology. Small molecule high throughput screening in human induced pluripotent stem cell-derived cells with the intent of identifying novel therapeutic compounds is starting to influence the drug discovery process; however, the use of these cells presents many high throughput screening development challenges. This technology has the potential to transform the way drug discovery is performed.

Highlights

Two major approaches to the discovery of small molecule drugs are generally being pursued: target-based and phenotypic
Clear limitations are associated with these models, including the increasingly documented lack of human disease relevance of the former and the very limited availability of the latter, with only few specific cell types being accessible from patients in significant numbers [14, 15]
Because human induced pluripotent stem cells (hiPSCs) can be generated from postnatal cells, it is possible to make human pluripotent stem cell lines from selected patients with relevant thoroughly sequenced genotypes, well characterized disease, and/or known positive/negative response to drug(s)

Summary

Introduction

Two major approaches to the discovery of small molecule drugs are generally being pursued: target-based and phenotypic. Mounting evidence suggests that capturing the biological complexity of the disease state in the earliest in vitro assays results in better clinical translation [10] This has driven a renewed interest in the use of physiologically relevant models in the drug discovery process [11,12,13]. They attributed their findings to shortcomings in the earlier assays to reflect the human disease because positive and negative findings in this assay correlated with positive and negative outcomes in human clinical trials These experiments have helped lay the conceptual groundwork for small molecule screens in hiPSC-derived cells with direct applicability to identifying novel compounds with symptom- or disease-modifying properties

Objectives

Conclusion