Hit Discovery and Structural Design Group

One of the key steps in target-directed cancer drug discovery is the identification of small molecule compounds (hits) that inhibit the activity of validated target proteins. This can be achieved by high-throughput screening of large lead-like compound collections using appropriate biochemical and cell-based assay formats that report the activity of the drug target, or by screening small compound libraries of low molecular weight molecules (fragments) using very sensitive biophysical techniques and high concentration biochemical assays.

The role of the Analytical Technology and Screening group is to establish, validate and run high-throughput and fragment screens on cancer drug targets under study at the Centre for Cancer Drug Discovery, and to carry out the initial characterisation of the hits obtained. Presently, we have a screening library of approximately 220,000 lead-like compounds, which we developed with our partner organisation Cancer Research Technology.

In addition, we have developed a fragment library of more than 2,000 compounds. Once progressible compound series have been identified, the group is involved in informing medicinal chemistry aimed at understanding and improving the pharmaceutical properties of the hits generated.

In addition, mechanistic endpoint assays are developed to support the CTU's drug discovery projects into clinical evaluation. These assays include, high-throughput phenotypic assays based on standard ELISA methodology and high content imaging assays based on the use of the InCell analyser.

The Structure-Based Drug Design Group is a joint initiative between the Divisions of Structural Biology and Cancer Therapeutics and consists of protein biochemists and protein crystallographers. The group has strong links with Medicinal Chemistry, In Silico Medicinal Chemistry and Biology teams within the CTU, and with the other crystallography team within the Division of Structural Biology.

The group uses biophysical techniques such as Tm-shift assays, Surface Plasmon Resonance, Isothermal Titration Calorimetry and High-Throughput X-ray Crystallography to characterise protein-ligand interactions of hit matter resulting from our fragment and high-throughput screens and continue to investigate these interactions as the hits progress to advanced inhibitors.

The activities of the Hit Discovery and Structural Design Team are underpinned by a state-of-the art protein production capability which is responsible for cloning, expression and purification of recombinant protein targets for the biophysical characterisation and X-ray crystallography as well as for the biochemical assays carried out in the Analytical Technology and Screening group. The team is experienced in construct design and has its own E. coli and insect cell expression facilities and a protein purification laboratory.

Structure-based drug design of cancer drugs

• Inhibitors of monopolar spindle 1 (MPS1) kinase
• Inhibitors of the KDM4/5 JmJC histone demethylases
• AGC kinase inhibitors

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Fragment-based lead discovery

• Fragment screening of Checkpoint kinase 2
• A fragment-based approach to target HSP70

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Assay development and screening

• Identification of IRE1 inhibitors

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