The landscape of early drug discovery is being reshaped by innovation in how we study absorption, distribution, metabolism, and excretion. DMPK is no longer a confirmatory discipline, it is a predictive science that informs chemistry, safety, and translational strategy from the very start. To keep pace, our assays must be integrated and more reflective of human biology.
In the DMPK team of o2h Discovery, we are committed to quickly translating bold new ideas into executable science on the bench. In this edition, we explore selected therapeutic areas and the DMPK strategies that underpin successful drug discovery. Each section introduces a therapeutic challenge, highlights commonly used assays, and features one assay in depth showcasing how it can provide actionable insights to accelerate informed decision-making throughout drug discovery.
We have a range of collaborative models and low friction start points you can start working with us including Kickstarter, Biology Match Funding and more collaborative models for capital-efficient ‘proof of concept’ such as Inflexion Tx. We are happy to use our experience with cascade and panel design and can get started on new projects on the bench in a matter of days/weeks.
At o2h Discovery, we seed new ideas in life science. We have a proprietary operating system for fast-tracking new ideas into a development candidate. The core is an integrated multi-modality drug discovery platform that combines novel capabilities with strategic partners embedded in an AI-enabled backbone to create a unique workflow. We are an insight-driven team based out of Cambridge, UK/USA and Ahmedabad, India.
1. Precision Oncology & Kinase-Targeted Therapies
Cancer drug discovery is increasingly driven by targeted therapies that inhibit dysregulated signalling pathways responsible for uncontrolled cell growth and survival. Developing successful kinase inhibitors requires balancing target potency with favourable physicochemical and DMPK properties to achieve adequate permeability, exposure and oral bioavailability.
Assays commonly used in kinase-targeted oncology programmes include:
Kinase Enzyme Activity Assays
ATP-Chemotherapy Response Assay (ATP-CRA)
ChameLogK Assay
ChamelogK Assay - Bioavailability of Beyond Rule of Five Compounds
The ChameLogK assay provides a quantitative assessment of molecular chameleonicity, a key property influencing the permeability and oral bioavailability of structurally complex molecules. When integrated with complementary DMPK and pharmacology data, it supports medicinal chemistry optimisation by helping balance permeability and solubility, particularly for Beyond Rule of Five (bRo5) modalities such as PROTACs, macrocycles and peptides.
Chameleonicity refers to a molecule's ability to adapt its conformation to different environments through the formation of intramolecular hydrogen bonds. ChameLogK quantifies this behaviour by integrating lipophilicity (BRlogD) and polarity (Δlog kwIAM) descriptors.
Leveraging literature-based methods, o2h Discovery has developed a reliable, high-throughput platform for rapid and cost-effective measurement of chameleonicity, enabling faster optimisation of bRo5 therapeutic compounds.
ChameLogK assay provides actionable insight into membrane permeability and distribution characteristics, supporting medicinal chemistry decisions aimed at achieving oral bioavailability and targeted tissue penetration.
Figure 1. Summary of chameleonicity across a range of chemical species
2. CNS Drug Discovery & Brain-Penetrant Therapeutics
Developing therapies for Central Nervous System (CNS) disorders requires drug candidates that can effectively cross the blood-brain barrier and achieve adequate exposure within the brain. One of the primary challenges is transporter-mediated efflux, where proteins such as Breast Cancer Resistance Protein (BCRP) can actively restrict drug accumulation within the brain. To address these challenges, researchers use in vitro permeability and transporter assays to predict brain penetration, efflux liability and developability of CNS drug candidates.
The MDCK-BCRP assay is a key in-vitro tool used to identify whether a compound is a substrate of the Breast Cancer Resistance Protein (BCRP), an important efflux transporter influencing drug absorption, distribution, and brain penetration. Using MDCK cells transfected with the human BCRP gene, the assay measures directional permeability across cell monolayers to determine active efflux. A high efflux ratio that is reduced in the presence of a BCRP inhibitor confirms substrate behavior.
Through bidirectional permeability and efflux ratio analysis, the assay identifies whether a molecule acts as a BCRP substrate or inhibitor, providing valuable insight into:
Access a range of ADME assays through our points-based programme – a simple, cost-effective way to gain the flexibility and economies of scale you need, without repeated paperwork.
3. Covalent Drug Discovery Across Therapeutic Areas
Targeted covalent ligands are increasingly being explored across multiple therapeutic areas including oncology, immunology, infectious diseases and neuroscience to achieve prolonged target engagement and improved pharmacological activity. A key challenge during lead optimisation is balancing effective covalent binding with minimising the formation of reactive metabolites that may contribute to off-target toxicity. Early assessment of glutathione reactivity enables medicinal chemists to identify potential safety liabilities and optimise compounds before advancing into more resource-intensive studies.
The GST + GSH stability assay is important because it helps identify reactive metabolites that can cause drug-induced toxicity early in development. Many compounds undergo metabolic activation by liver enzymes (such as CYP450s) to form electrophilic intermediates that can bind covalently to proteins, DNA, or other cellular components, leading to adverse effects like hepatotoxicity or idiosyncratic reactions. By trapping these reactive species as GSH adducts and detecting them using LC-MS/MS, scientists can predict potential safety risks, understand metabolic “hot spots,” and make structural modifications to improve compound safety before advancing to costly in vivo or clinical studies. To investigate this, our GST + GSH stability assay, powered by LC–MS/MS, screens compounds for their tendency to form glutathione adducts via glutathione-S-transferase (GST) pathways.
The GST + GSH assay provides early insight into:
Bioactivation risks and reactive metabolite formation
Metabolic soft spots for medicinal chemistry optimisation
Safety liabilities that might emerge in preclinical models
Integrating this data in early discovery supports structure refinement and safer candidate progression.
Figure 3: Researcher working on the LC-MS platform at the Shirish Research Centre.
Integrated DMPK Services
These novel assays are part of o2h Discovery’s integrated DMPK platform, which seamlessly connects:
In-vitro ADME screening
In-vivo pharmacokinetic studies
Data interpretation and medicinal chemistry feedback
Our integrated in-vitro ADME and in-vivo Pharmacokinetics (PK) services are designed to bridge this gap enabling faster, and more confident transitions from hit identification to candidate nomination. Our integrated model ensures efficient communication between chemistry, biology, and DMPK enabling faster iterations, smarter design, and higher-quality decision-making throughout the drug metabolism and toxicity (DMT) cycle.
Ready to simplify your ADME workflow? Contact us about our easy-access points-based system for flexible cost-effective ADME assays at your fingertips.
