Drug Discovery
Optimising clinical leads, 3D cell culture systems
Optimising Clinical Leads: Increasing drug discovery success with 3D cell culture systems

Optimising Clinical Leads: Increasing drug discovery success with 3D cell culture systems

By Dr Richard M. Eglen, Dr Feng Li and Dr Tony Frutos
Winter 2018/19

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.

Advances in three-dimensional (3D) cell culture systems are helping address the above challenges and improve the likelihood of success for pipeline assets. From disease modelling and validation of novel targets to screening 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 culture 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 opportunities, challenges and future of 3D cell culture. The need for greater biological relevance was cited by many survey respondents as the driving force behind adoption of 3D cell culture systems with the most common applications being disease modelling, 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 soluble gradients and possess an unphysiological apicalbasal polarities. With use of 3D cell culture systems, along with matrices and scaffolds that simulate the extracellular matrix (ECM), tissue microenvironmental 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...

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