Cell Culture
Optimising clinical leads: increasing drug discovery success with 3D cell culture systems
Drug candidates often fail in the clinic for two reasons: they lack efficacy or possess an adverse toxicity profile. These failures can come at a high cost, especially when drug candidates have already progressed along the development pipeline to clinical trial.
A
dvances in three-dimensional (3D) cell culture systems are helping address the above challenges and improve the likeli-
hood of success for pipeline assets. From disease modelling and validation of novel targets to screen- ing for safety and efficacy, 3D cell cultures offer the exciting potential for the development of novel medicines and increased productivity. This article describes the benefit of 3D cell cul-
ture on the drug discovery workflow, with a focus on lead optimisation in which compounds are assessed for their potential metabolic liability and off-target toxicities. The powerful combination of human-induced pluripotent stem cells (HiPSCs) and 3D cell culture systems are also highlighted.
The 3D advantage A survey was recently conducted of researchers in academia and industry to explore the opportuni- ties, challenges and future of 3D cell culture. The need for greater biological relevance was cited by
Drug Discovery World Winter 2018/19
many survey respondents as the driving force behind adoption of 3D cell culture systems with the most common applications being disease mod- elling, oncology and toxicity screening. The advantage of 3D cell cultures for delivering
greater biological relevance is clear. When grown in two-dimensional (2D) monolayers, cells reside on a continuous layer of matrix, are not exposed to solu- ble gradients and possess an unphysiological apical- basal polarities. With use of 3D cell culture systems, along with matrices and scaffolds that simulate the extracellular matrix (ECM), tissue microenviron- mental cues are retained. Local soluble chemicals and the ECM environment facilitate correct cellular differentiation, function and communication. As a result, cells grown in 3D cultures more closely mimic in vivo physiology in terms of morphology, structural complexity and phenotype. When applied to drug discovery and safety pro-
filing, the advantages of human 3D model systems are clear:
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By Dr Richard M. Eglen, Dr Feng Li and Dr Tony Frutos
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