Activity-directed discovery of chemical probes of protein kinase biology

Lead Research Organisation: University of Leeds
Department Name: Astbury Centre

Abstract

Background:
The availability of high quality probes can address the highly unsystematic historic exploration of the biology of proteins. This project will focus on ATP-competitive inhibitors of a protein kinase that would enable interrogation of its role protein kinase in key biology mechanisms.

In preliminary work, fragments that bind the protein kinase have been identified. However, structure-based inhibitor discovery has been hampered by the inability to crystallise the kinase in complex with fragments. The project will therefore exploit activity-directed synthesis (ADS), Nelson's discovery approach that can enable productive fragment elaboration in the absence of structural information. The resulting probes will reveal insights into the cellular function of the protein kinase e.g. in conjunction with cell biology collaborators.

Objectives:
1. To identify an expanded range of binding fragments;
2. To exploit ADS in the discovery of potent and selective ATP-competitive kinase inhibitors;
3. To determine the structural basis of small molecule inhibition;
4. To exploit the small molecule inhibitors as chemical probes of biological mechanisms.

Novelty and timeliness:
The discovery of potent and selective inhibitors of some protein kinases is challenging due to specific active site features; and a lack of structural information. ADS is a capability that is unique worldwide, and can support ligand discovery in the absence of structural information. Here, ADS will be exploited to discover the first potent and selective modulators of a specific protein kinase.

Experimental approach:
1. Biophysical techniques to discover and characterize binding fragments;
2. Activity-directed synthesis to support fragment-based probe discovery;
3. Protein crystallography to reveal the structural basis of inhibition;
4. Preliminary cellular biology studies enabled by the novel probes.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 01/10/2015 30/09/2023
1939281 Studentship BB/M011151/1 01/10/2017 30/09/2021 Christopher Arter