Drug Discovery

Target Validation:

We work with you to demonstrate the disease relevance of your target and to elucidate its druggable attributes. Approaches we use include:

• Genetic manipulation of the target
• Investigating the consequences of target manipulation on downstream pathways
• Omics profiling in relevant cell systems
• In vivo model development to perform early proof of concept studies
• Identification of appropriate biomarkers

Hit identification and expansion:

We are dedicated to identifying high-quality hits and hit series. We can employ one or more hit finding strategies utilising a varied range of assays including biochemical and cell based. Approaches we use include:

• High-throughput screening using our customers’ or our own diverse library of over 320,000 compounds
• Virtual screening
• Fragment-based screening
• Phenotypic screening
• NMR screening
• Phage display

Hit to lead:

The goal of this stage is to select the most promising series through limited structure–activity relationship (sar) studies. Approaches we use include:

• Computational chemistry to cluster the active hits into families
• Medicinal chemistry and synthetic chemistry to design and synthesize new compounds based on the active hits and their chemotypes
• Implementation of an efficient screening cascade, bringing together an interdisciplinary team for rigorous primary and secondary testing to assess potency, selectivity, on and off target activity and early ADME

Lead optimization:

Here we extensively optimize, in parallel, both the biological activity and the properties of the lead series, again utilising a dedicated screening cascade but with a broader suite of assays and screens and clear go/no go decisions. Approaches we use include:

• Multi-parametric optimization of promising series
• Primary and secondary screenings to assess potency and selectivity both in enzymatic and cell based assays
• Medicinal chemistry SAR, design, synthesis and optimization of the lead series
• Pharmacokinetic (PK) and Pharmacokinetic / Pharmacodynamic (PK/PD) animal studies, including metabolite ID
• In vitro and in vivo assessment of metabolism and off-target activities
• An in vitro blood-brain barrier model generated from human induced pluripotent stem cells to predict brain penetration
• NMR support for structural biology evaluations (structural characterization, aggregation state, target/ligand interaction)
• Metabolomics and biomarker ID in animal and human biofluids
• Formulation support
• Scale-up synthesis for small molecule compounds (up to 1kg scale)
• Chemistry support and route scouting for synthesis optimization
• Separation of chiral compounds at the preparative scale
• Crystalline salt selection
• Parallel and rapid analog synthesis supported by automated purification systems

Candidate nomination:

In this phase we characterize the most promising leads from the lead optimization phase with the aim of producing a data package ready to submit for investigational new drug (ind). Approaches we use include:

• Full characterization of compounds for promotionto development
• Focused ADME around a specific dosage form
• Early toxicity studies including genotoxicity and carcinogenicity