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 or other ATP-dependent enzymes, 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.
Medium Rings and Macrocycles
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 have used 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 medium-ring containing cembranoid marine natural products.
We have developed efficient synthetic routes for the enantioselective assembly of a hexahydroisobenzofuran scaffold, and have explored a variety of medium-ring and macrocycle forming reactions to increase the diversity of the library. The new synthetic compounds bridge the chemical space between the complex natural products and typical medicinal chemistry screening libraries.
In a further development of this project, we are applying the synthetic methods to make medium-ring containing analogues of nucleosides, to study how unusual conformational restrictions of these important natural substrates can be exploited to generate new scaffolds for drug design.
A library of hexahydroisobenzofuran 2,11-cyclised cembranoid analogues.
Kinase-focused Heterocyclic Libraries
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.
We developed solution-phase parallel syntheses to construct diverse libraries of novel templates that mimic the interactions of indirubin with protein kinases, and used a microfluidic assay platform to show that a water soluble pyrazolopyridine library has a wide range of kinase inhibitory activities.
A library of pyrazolopyridone kinase inhibitors.
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 have developed new synthetic routes to allow rapid and diverse substitution of the spirocyclic scaffolds.
A library of spirocyclic kinase inhibitors.
E3 Ligase Targeting Compounds
Many proteins are degraded by the proteasome following the attachment of ubiquitin tags by E3 ubiquitin ligase complexes, which recognise certain sequences in the target proteins. Small molecules can bind to some E3 ligases and change the repertoire of proteins they recognise.
This hijacking of the ubiquitin-proteasome pathway provides a way to select proteins for degradation that would otherwise be unaffected. We are assembling libraries of compounds that bind selected E3 ligases and redirect their substrate specificity to degrade proteins relevant to cancer.