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Fragment-based Inhibitor Discovery

In collaboration with experts in structural biology at The Institute of Cancer Research and external partner organisations, we have successfully applied fragment-based approaches to our kinase drug discovery projects, leading to clinical candidate inhibitors of PKB and CHK1. Fragment hits must be grown to fill their binding sites, involving substantial changes in the size and functionality of the molecules.

We have shown how fragment growing can be directed to retain or change the selectivity of the inhibitors between the fragments and the larger lead compounds. Kinase proteins have well defined binding sites and a limited range of flexibility, and we are also interested in applying fragment-based drug discovery to more challenging target proteins with greater conformational flexibility or less obviously tractable binding sites.

Fragments figure

Retaining and enhancing fragment kinase selectivity in the evolution of CHK1 inhibitors.

HSP70 Inhibitors

The HSP70 family of molecular chaperone ATPases are expressed in response to heat shock and other cellular stresses. In complexes with other proteins, the HSP70 proteins protect misfolded or unfolded client proteins from degradation, and refold them to restore client activity. HSP70 isoforms are overexpressed in many cancers.

In collaboration with Professor Paul Workman and Dr Rob van Montfort we are applying fragment and structure-based approaches to the discovery and optimisation of inhibitors of HSP70. A key challenge is to understand the conformational flexibility of the HSP70 protein and how this affects the ligand binding sites.

HSP70 Figure

Fragment bound to HSP70 nucleotide binding domain.

Tankyrase substrate binding antagonists

ADP-ribosylation entails the transfer of ADP-ribose onto substrate acceptors by poly(ADP-ribose)polymerases (PARPs), enzymes that construct linear or branched chains of poly(ADP-ribose). Tankyrase is a PARP that modifies a large number of protein targets involved in a wide variety of biological functions, including DNA repair and oncogenic signalling.

In collaboration with Dr Sebastian Guettler (Division of Structural Biology, The Institute of Cancer Research) we have used NMR fragment-based approaches to discover inhibitors of the protein-protein interaction between tankyrase and its substrates, thereby targeting the enzyme outside its catalytic PARP domain.

IanCollins NMR

Protein NMR chemical shift perturbations observed on the binding of the fragment 9 to15N-labelled Tankyrase ARC4 domain locate the binding site of the fragment to a hydrophobic cleft in the peptide substrate binding region.