Optimisation of small molecule inhibitors for effective targeting of phospholipase C gamma in T-cell lymphoma

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Progress in cancer treatment very much varies between different cancer types. For many types of cancer, the current interventions considerably prolong lives of patients, other cancers, including T-cell lymphomas, have an unmet clinical need. T-cells lymphomas include adult T-cell leukemia/lymphoma (ATL), highly aggressive malignancy that arises in a subset of carriers of human T-cell lymphotropic virus type 1 (HTLV-1), following subsequent accumulation of somatic mutations. The median overall survival of aggressive subtypes is ~9-13 months and depressingly, with current treatment options, this survival rate has remained largely unchanged in the past 30 years. There is a clear and urgent need to identify and conduct clinical trials of novel therapies for this disease. Although cancer develops through progressive somatic mutations, numerous preclinical and clinical studies have shown that cancer cells depend on relatively few genetic driver events. Recent studies have provided comprehensive analyses of the genetic changes in ATL and other T-cell malignancies, highlighting such potential oncogenic driver mutations. Frequent mutations affect different components important for T-cell functions and, in particular, cell signalling components linked to specific T-cell receptors. The most frequently mutated PLCG1 gene encodes phospholipase C gamma 1 (PLC?1), an enzyme involved in intracellular signal transduction. There are several lines of supporting evidence that mutated/activated variants of PLC?1 contribute to the properties of the malignant, ATL cells. Considering that cell signalling components are the molecular targets of most currently used medicines, largely based on small-molecule inhibitors, this so far unexploited target provides an opportunity to develop much needed novel therapies for ATL, other T-cell lymphoma and several other diseases linked to activated variants of PLC enzymes. The overall aim of our continuous efforts is to generate a small molecule drug that can be used as a single agent, or as a combination agent, in different lines of therapy. As a first step, we recently completed large-scale screens for inhibitors of a frequently mutated PLC?1 variant in T-cell lymphoma. We have identified several series of promising compounds for further optimisation and drug development. We now plan to expand a subset of hit compounds and identify more potent and more selective PLC inhibitors needed for further biological evaluation and preclinical studies. To achieve this, we propose to apply medicinal chemistry, where design of new compounds is assisted by our structural, biophysical, and computational tools. Together with already available analogues, we will test these new compounds in our established in vitro and cell-based assays. The combined expertise and track record of investigators and their partners, involved in our previous and this proposed project, extensively covers molecular and functional properties of the target, medicinal chemistry and drug discovery, and preclinical and clinical aspects of ATL. As a new component of this proposal, we also include expertise in artificial intelligence-based methods related to drug discovery. The step covered by this proposal is necessary to obtain definitive answers about achievability of desired improvements, which will lead to the next established stages in progression through a drug discovery programme.