Discovering inhibitors of gain-of-function Phospholipase C gamma1 for T-cell lymphomas

Lead Research Organisation: University College London

Abstract

This proposal is aimed at creating medicines that can control a protein called Phospholipase Cgamma1, for use in the treatment of a subtype of blood cancers, known as T-cell lymphomas. It is based on clinical insight provided by our team, including those treating patients with this disease and the recognition of a need for improved therapies. We have long-term expertise on the proposed target molecule. We believe we have established a set of interconnected experimental and screening approaches that will provide the route to new treatment options, and would now like to turn these advances into a medicine, with the help of the access to the AstraZeneca screening collection to start our drug discovery efforts. Although this proposal focuses on T-cell lymphomas, drugs obtained for this purpose will be also useful for a range of other diseases caused by deregulation of the same target.

Technical Summary

We propose to generate inhibitors to target gain-of-function PLCgamma1 variants in the context of dysregulated T-cell signalling, for the treatment of T-cell lymphoma. This is a relatively rare cancer, with dismal prognosis for more aggressive forms. A need remains for a selective agent that targets biology specific to these cells.
This proposal is based on clinical insight provided by our team. Dr Lucy Cook is not only treating the patients but recently led a consensus for a best practice and has opened clinical trials while Professor Charles Bangham has the long-term involvement in defining the mechanism of leukaemogenesis in T-cell lymphoma (in particular ATL). Notably, the proposal also exploits our expertise in PLCgamma enzymes in physiology and pathology and a focus on structural and mechanistic aspects of their regulation, provided by the Katan team. Based on our recent structural insights (collaboration with AstraZeneca) and further characterization of the variants supporting a distinct conformation of gain-of-function proteins, we are in a leading position to take the proposed approach.
This proposal also builds on our current, MRC-funded project (Assessing new therapeutic opportunities linked to TCR signalling in mature T-cell lymphomas with unmet need) led by Professors Katan and Bangham. Dr Richard Angell has participated in generating leads for a number of novel targets at UCL, including two Open Innovation collaborations with AstraZeneca. The team has extensive experience of working effectively with the AstraZeneca team.
We propose to carry out a high throughput screen for PLCgamma inhibitors using the AstraZeneca proprietary compound library. Primary assay development has been completed by the Academic Partners (Dr Trevor Askwith, Dr Tom Bunney) and the downstream cascade assays identified. Small-scale reagent generation has also been performed and we are in a position to generate the reagents required for a high throughput screen."

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