Histone acetyl transferase (HAT) inhibitors in COPD/asthma

Our project aims to discover new drug leads for chronic inflammatory lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Current anti-inflammatory drugs, such as corticosteroids, are ineffective in COPD and poorly effective in a considerable proportion of chronic asthma patients, and new therapeutic strategies are urgently required. We believe that redressing imbalances of gene transcription in the cells of affected airways tissues can be achieved with inhibitors of a group of enzymes called histone acetyl transferases (HATs) in order to alleviate disease and to restore sensitivity to corticosteroids. We will identify HAT inhibitors using an interdisciplinary approach that brings together expertise in transcription regulation biology, respiratory medicine and cell biology, natural products screening, and medicinal chemistry at the University of Nottingham and the Strathclyde Institute for Drug Research. Using appropriate biochemical and cellular test systems, we shall screen an extensive, chemically diverse, and biodiverse natural products extract collection. Natural products have traditionally been a rich treasure trove for biologically active molecules. Starting from promising compounds identified in these screens, medicinal chemistry will then be used to develop drug candidate compounds with the desired properties in terms of potency, specificity, and pharmacological action.

This 3-year proof-of-concept project application relates to the MRC PSCSB call for proposals relevant to the development of new diagnostic and therapeutic approaches for chronic inflammatory lung diseases, including asthma and COPD. The hypothesis for the proposed work is that therapeutic restoration of histone acetylation balance in the cells of affected tissues in inflammatory lung disease can be achieved with inhibitors of histone acetyl transferases (HATs) in order to alleviate disease progression and restore corticosteroid sensitivity. The level of cellular histone acetylation is determined by the opposing actions of HATs and histone deacetylases (HDACs), which function as transcriptional coregulators. Oxidative stress is the main cause for the initiation of the inflammatory response in chronic inflammatory lung diseases through activation of pro-inflammatory transcription factors by enhanced recruitment and activation of transcriptional coactivators that possess HAT activity.
We aim to identify small-molecule HAT inhibitors using an interdisciplinary approach that brings together expertise in transcription regulation biology, respiratory medicine and cell biology, natural products screening, and medicinal chemistry at the University of Nottingham and the Strathclyde Institute for Drug Research. We shall develop and deploy cell-based HAT reporter assay screens of an extensive, chemically diverse, and biodiverse natural products extract collection. The choice of a natural products library is predicated on the paucity of currently known HAT inhibitors and the fact that most of the few known inhibitors are in fact natural products. Hit compounds will be identified through iterative deconvolution by extract fractionation, structure elucidation, and secondary screens, including biochemical HAT assays. Hit-to-lead optimisation medicinal chemistry will be carried out and lead compounds will be profiled extensively in terms of target and cell potency, selectivity, specificity, and pharmacological action, including the use of human airway cells.
The goal of the project is to provide pharmacologically and pharmaceutically suitable HAT inhibitor lead compounds that can subsequently be used for proof-of-principle studies in animal models of COPD and asthma, and that may represent candidates for future drug development. Support is requested for staffing at a level of 6.5 person years and a commensurate consumables budget to achieve this goal.