Cell-based drug discovery | Why human iPSC-derived cells are gaining ground

Despite decades of innovation, attrition rates in drug discovery remain unacceptably high: fewer than 1 in 10 candidates entering clinical trials reach patients, and central nervous system (CNS) programs fail up to 90% of the time^1,2. The root cause lies in the translational gap: current models fail to reliably predict human outcomes. Closing this gap requires defined, human-relevant in vitro systems that can support confident decision-making across the discovery workflow.

Human iPSC cell culture is helping to answer this need by providing a foundation for robust phenotypic screening across target ID, assay development, hit-to-lead, lead optimisation, and safety profiling.

The need for better cell-based assays

Cell-based assays in drug discovery have long relied on traditional models. While these systems remain workhorses of preclinical drug discovery, their limitations are now clearer than ever:

• Immortalised lines are robust and scalable, but their lack of phenotypic fidelity means signals often don’t translate, creating false positives and wasted effort downstream.
• Animal primary cells capture some physiology, but their variability, and species differences make it hard to generate reliable, human-relevant data at scale.
• Conventional iPSC-derived models offer human-derived cells, but poor purity and batch variability add noise, making it difficult to compare results across experiments or sites.

Human iPSC-derived models: progress and limitations

Human iPS cell culture is already proving valuable in cell-based drug discovery. Unlike immortalised lines or animal-derived primary cells, they provide access to diverse human cell types, including neurons, cardiomyocytes, and hepatocytes. This makes them attractive for early-stage research, where capturing human-relevant biology is critical.

Across the discovery workflow, iPSC-derived cells are being applied in diverse ways, such as:

• Target identification and validation
  Human iPSC-derived cells add value at the initial stages of drug discovery by offering a representation of human biology and disease in vitro, supporting accurate drug development from start to finish. iPSC-derived cells are compatible with genome editing approaches such as CRISPR, which enable pathway analysis and functional validation of targets directly in a human cellular context⁶. High-content screening (HCS) has also been widely used with iPSC-derived cells, combining automated imaging and quantitative analysis to measure reporter signals, morphology, and subcellular localisation⁷. 
• Assay development and optimisation
  Using human iPSC-derived cells allows assays to be built around human-relevant pathways, ion channels, receptors, and transcriptional programs. Consequently, assay parameters (e.g., compound dosing, time course, endpoints) can be optimised based on human kinetics and signalling. For example, iPSC-derived neurons and cardiomyocytes are used in electrophysiology and calcium flux assays to measure excitability, ion channel function, and network activity⁸. These models also support optimisation of HCS protocols and real-time impedance assays to monitor morphology and proliferation⁷.
• Hit-to-lead screening
  During the hit-to-lead stage, iPSC-derived cells add human relevance for establishing structure–activity relationships (SAR) between chemical structure and biological activity. iPSC-derived hepatocytes are being introduced for use in metabolism and drug–drug interaction studies, including cytochrome P450 induction and inhibition⁹. As phenotypic and neuroinflammation assays evolve to improve physiological relevance, scientists are increasingly incorporating iPSC-derived neuronal and immune cells, often combined with viability or cytotoxicity readouts such as LDH release or apoptosis assays¹⁰. 
• Lead optimisation
  iPSC-derived sensory neurons characterised via multi-electrode arrays (MEA) and stimulus responses are being used to model pain pathways and evaluate compound effects^11,12. Many iPSC-derived cell types exhibit measurable physiological activity (e.g., neuronal firing), enabling optimisation for distinct functional readouts across targets and compound classes.
• Safety and toxicology screens
  iPSC-derived cardiomyocytes are widely used in the early stages of preclinical safety studies to assess pro-arrhythmic risk¹³. The CiPA initiative exemplifies this integration: over the past decade, iPSC-derived cardiomyocytes have been characterised across multiple sites and assay platforms using reference compounds, helping to standardise and enhance early-stage pro-arrhythmic risk assessment¹⁴. Hepatocyte models have also been benchmarked in drug-induced liver injury (DILI) studies, showing time- and dose-dependent toxicity consistent with known clinical outcomes¹⁵. 

These examples highlight how iPSC-derived cells complement traditional systems, enabling scientists to generate human-relevant data earlier in discovery. However, most conventional iPSC-derived cells rely on directed differentiation protocols, which can be slow, technically demanding, and prone to variability—leading to batch-to-batch inconsistency that limits reproducibility and scalability in phenotypic screening¹⁶. Combined with persistently high clinical failure rates, these challenges highlight the urgent need for more consistent, human-relevant iPSC-derived cells^1,2. Addressing these bottlenecks requires solutions that preserve human relevance while eliminating variability and scale constraints.

 ioCells in cell-based drug discovery

The limitations of conventional iPSC differentiation can undermine otherwise powerful in vitro models. ioCells address these challenges through deterministic cell programming with opti-ox™, a gene targeting strategy that ensures every iPSC in a culture is programmed to the same defined cell identity.

ioCells are already being applied in key cell-based assays in drug discovery, across the workflow in areas where reproducibility and scalability are most critical: 

• Target identification and validation
  CRISPR-Ready ioCells are used in functional genomics studies, where reproducibility is essential for interpreting large-scale perturbation screens. For example, CRISPRko-Ready ioMicroglia engineered to express Cas9 have supported pooled CRISPR knockout experiments to identify regulators of immune activation pathways.
• Assay development and optimisation
  Assay reproducibility depends on consistent cell populations. ioCells, characterised for marker expression and function, have been applied in both monoculture and multi-cell culture systems. For example, ioGlutamatergic Neurons have been incorporated into 3D neuronal microtissues that retain functional stability across experiments.
• Hit-to-lead screening
  Human ioMicroglia have been used to study chemotaxis, cytokine release, and phagocytosis. In these assays, reproducibility across batches reduces variability, helping researchers distinguish between compound effects and noise.
• Lead optimisation
  ioCells have supported longitudinal electrophysiology and imaging studies, where consistent function over time is necessary for comparing candidate effects. In well characterised, defined and physiologically relevant disease models, such as ioGlutamatergic Neurons carrying ALS mutations, robust electrophysiological assays reproducible MEA  support a more confident interpretation of drug responses.
• Safety and toxicology screens
  Human ioHepatocytes are being developed and applied to advance in vitro safety testing, providing defined and reproducible human models for assessing drug metabolism and hepatotoxicity. Their stable function and gene expression enable long-term assays for DILI, supporting consistent and translationally relevant results. Recent work highlights how ioHepatocytes are bridging discovery and toxicology research—accelerating the development of more predictive human liver models for safety assessment.

Challenges of existing liver models | Comparing hepatocyte models highlights the need for scalable, reproducible human systems. As the liver is central to toxicity, introducing consistent and defined iPSC-derived ioHepatocytes earlier can improve safety insights and accelerate drug development timelines.

Key benefits of next-generation iPSC models 

Unlike conventional directed differentiation, which can be long, complex, slow, and variable, opti-ox enables the rapid generation of consistent, defined human cell types. ioCells offer researchers control and confidence by providing consistent, specified inputs for discovery workflows.

• Defined identity: every cell is programmed to the same fate, with <1% differential gene expression between lots.
• Consistency at scale: billions of consistently programmed cells can be generated in a single manufacturing run, ensuring supply for extended phenotypic screening campaigns.
• Ease of use: cells arrive cryopreserved and require a simple protocol using an open-source medium to get started.
• Assay versatility: ioCells support applications from functional genomics to complex co-culture electrophysiology.

The future of cell-based drug discovery

The challenge facing modern cell-based drug discovery is not simply choosing between immortalised lines, primary cells, or iPSC-derived models, but ensuring that any system can deliver reproducible, scalable, and human-relevant data that improves translational success.

Human iPSC-derived cells have already demonstrated their value across the workflow, from target identification to safety profiling. Yet conventional differentiation workflows remain variable, limiting their impact on large-scale discovery. Deterministically programmed ioCells address this gap by combining the human relevance of iPSC-derived systems with the reproducibility required for phenotypic screening at scale.

This direction is reinforced by the broader shift in the field: regulatory agencies and funders are explicitly prioritising human-based models. Initiatives such as the FDA’s Roadmap to Reducing Animal Testing³ and the NIH Complement-ARIE program¹⁷ show that reproducibility and human relevance are no longer optional, but expected.

As attrition rates remain high, the need for models that better predict human outcomes is urgent. ioCells represent one step toward that goal: not just an alternative to existing systems, but part of a new standard in cell-based drug discovery.

References

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