Novel Kinase Screening Libraries

Medicinal Chemistry Team Two

Section: Cancer Research UK Cancer Therapeutics Unit

We have ongoing projects on the design and preparation of medium-sized libraries of novel, lead-like and drug-like compounds. The libraries are particularly intended to target kinases, using insights from our drug discovery projects, and thus augment our screening collection in this important area. The library projects 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 highly selective and 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: Mimicking the Indirubin Motif with Novel, Drug-like Scaffolds

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. Solution-phase parallel syntheses have been developed to construct diverse libraries based on the novel templates. We are assessing the library compounds both for their kinase inhibitory activity using microarray and other high-throughput technologies.

Kinase Targeted Libraries: A Three-Dimensional Protein Kinase Inhibitor Library Based on Azacycles and Azabicycles

The design of selective kinase inhibitors that can discriminate between closely related enzymes is a major challenge for current anticancer drug discovery. Using insights from our structure-based drug discovery programs targeting kinases, this project explores the structure-selectivity relationships that arise from targeting non-conserved features in the ribose-binding and phosphate-binding regions of the enzymes. The library is based on saturated nitrogen heterocycles that provide scaffolds with well-defined geometries to explore the enzyme active sites.