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H2020Individual fellowship2016–2018

jamclay · Chemical Tools to Probe the Role of Bromodomains in the Parasite Trypanosoma cruzi

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2016-03-24 → 2018-03-23
EU contribution
€183,455
Participants
1
Scheme
MSCA-IF-EF-ST

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Results in brief

Chemical Tools to Probe the Role of Bromodomains in the Parasite Trypanosoma cruzi

Recently the development of small molecule bromodomain ligands has been the focus of significant attention from the medicinal chemistry community. The bromodomain and extra C-terminal domain (BET) family of bromodomain-containing proteins (BCPs) have emerged as important therapeutic targets for cancer and inflammation therapy, and focus has now turned to developing ligands for non-BET BCPs, to determine their function and therapeutic potential. Bromodomains are epigenetic reader proteins that bind to acetylated lysine (KAc) residues, these fundamental interactions play a key role in regulation of important transcriptional protein-protein interactions that regulate the expression of certain genes. Here we report the design, synthesis, and biological evaluation of a range of potent and selective ligands for the CREBBP bromodomain, which is a key transcriptional co-activator. Objective 1. Our initial hit molecule contained a metabolically unstable dihydroquinoxalinone acetyl-lysine mimicking 'head group' and an aryl amide. The acetyl-lysine mimicking 'head group' was developed into a more metabolically stable benzodiazepinone it's ring expanded head group containing an additional CH2 reduces degradation, as oxidation of dihydroquinoxalinone gives an aromatised quinoxalinone with reduced activity. Objective 2. Although improving metabolic stability introduction of the benzodiazepinone caused the molecules internal hydrogen bonding network to change, a reduced affinity binding conformation now formed in solution. The internal hydrogen bonding in the presence of the benzodiazepinone head group was a hinderance. Thus we re removed the aryl amide and replaced it with an E-alkene a classical amide bio-isostere.

Data: CORDIS, © European Union

Project objective

Lysine acetylation is a key protein post-translational modification (PTM) found throughout the cellular environment and across the range of species. This PTM is dynamic, with histone acetyl transferases (HATs) acetylating lysine, and histone deacetlyases (HDACs) reversing the modification. In addition, proteins modules bromodomains, have been identified that bind to acetylated lysine (KAc) and mediate protein-protein interactions. In humans, bromodomains exist as part of larger proteins, many of which are involved in transcriptional regulation. Bromodomains contain a KAc-binding pocket for which small molecule ligands have been identified. These ligands prevent the interaction of bromodomains with KAc and have been invaluable in dissecting the fundamental biology mediated by bromodomain-containing proteins (BCPs). We and others have developed potent ligands for the human bromodomain and extra C-terminal domain (BET) bromodomains. These compounds have antiproliferative effects in cancer cells lines and modulate inflammation and atherosclerosis. This work led to an explosion of interest in developing BET bromodomain inhibitors, resulting in 5 compounds in clinical trials. Despite rapid progress in understanding the role of human bromodomains, their function in other species is poorly understood. Given the fundamental role played by bromodomains in humans, we hypothesise that BCPs will play equally important roles in other organisms.To understand the role of non-human bromodomains we will develop small molecule probes to study the function of BCPs in the parasite Trypanosoma cruzi. We have selected T. cruzi for two reasons: 1. Four BCPs (TcBDF1-4) have been discovered in T. cruzi; our collaborator Prof. Serra has cloned these proteins and we have the plasmids; 2. T. cruzi is the parasite that causes Chagas Disease and hence bromodomain ligands might ultimately represent a novel method of treatment for this disease.

Original text from CORDIS.

Participants

  • THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom

Links

Data: CORDIS, © European Union