Research Interest
New Screening Libraries for Anticancer Drug Discovery
We have ongoing projects on the design and preparation of medium-sized libraries of novel, lead-like and drug-like compounds. Many of the libraries are particularly intended to target kinases, using insights from our drug discovery projects, and contribute to our future screening projects in this important area. We also develop new synthetic chemistry relevant to drug design and the medicinal chemistry optimisation of anticancer drugs.
Kinase Targeted Libraries: New Macrocycles as Scaffolds for Selective and Multi-targeted Kinase Inhibitors
This project explores the hypothesis that functionalised macrocycles derived from established kinase inhibitor scaffolds will give structurally novel compounds with different intrinsic selectivity profiles and pharmacokinetic properties from the parent templates. The new macrocycles and general routes for their synthesis will be useful starting points for the rational design of either highly selective or specific, multi-targeted kinase inhibitors as anticancer drugs. The results of this project will provide new medicinal chemistry strategies for controlling kinase inhibitor selectivity and pharmacokinetics.
Kinase Targeted Libraries: Novel Pyrazolopyridones Inspired by Indirubin
The indirubin class of natural products are high affinity ATP-competitive kinase inhibitors, but the planar tetracyclic core leads to poor solubility and cell permeability. Suitable novel templates were identified through in silico docking that preserve the geometry and donor/acceptor properties of the indirubin motif, but possess more drug-like physicochemical properties. We developed solution-phase parallel syntheses to construct diverse libraries based on the novel templates. We have used a microfluidic assay platform to show that the pyrazolopyridine library has a wide range of kinase inhibitory activities, and have confirmed that the compounds are highly water soluble.
A novel library of pyrazolopyridone kinase inhibitors.
Kinase Targeted Libraries: Protein Kinase Inhibitor Libraries Based on Azaspirocycles
The design of selective kinase inhibitors that can discriminate between closely related enzymes is a major challenge for anticancer drug discovery. Using insights from our structure-based drug discovery programs targeting kinases, we have explored the structure-selectivity relationships that arise from targeting non-conserved features in the ribose-binding and phosphate-binding regions of the enzymes. This novel library design is based on spirocyclic nitrogen heterocycles that provide scaffolds with well-defined geometries to explore the enzyme active sites. In parallel, we are developing new synthetic routes to allow rapid and diverse substitution of the spirocyclic scaffolds.
Diversity-Oriented Libraries: Design and Screening of a Library of Cembranoid Analogues
Natural products and their semi-synthetic derivatives have provided many important anticancer therapies. Diversity-oriented synthesis has been proposed as one means to prepare libraries of non-natural molecules that can incorporate the structural complexity typical of natural products.
This project tackles the problem of how to use the structural complexity and diversity of natural products for novel drug discovery, while still retaining drug-like properties and synthetic tractability. In collaboration with Dr Florence Raynaud in the Drug Metabolism and Pharmacokinetics Group, we are using high-throughput assays for water solubility and membrane permeability to guide the design of a library of stereochemically complex compounds based on the structures of cembranoid marine natural products with anticancer activity. We have developed efficient synthetic routes for the enantioselective assembly of the core hexahydroisobenzofuran scaffold, and have explored a variety of medium-ring and macrocycle forming reactions to increase the diversity of the library.
A library of 2,11-cyclised cembranoid analogues.
