Chemical biology, medicinal chemistry and drug discovery
We continue to develop a range of chemistry-led approaches to interrogate novel targets/techniques for the treatment of disease. Our studies span efforts in curiosity-led basic science through to translational drug discovery. Representative examples include medicinal chemistry efforts towards a wide range of current and future drug targets in a range of diseases and the development of chemical biological tools (substrate ID reagents, proteomic profiling techniques, imaging agents, etc) that would enable better biological understanding of disease-related events.
Chemical Biology, Medicinal Chemistry and Drug Discovery
Therapeutics targeting transcriptional pathways
Tight control of gene transcription is essential for cellular development and the establishment of cellular identity. Dysregulation of transcriptional programmes is a common mechanism that leads to the development and maintenance of disease, especially cancer. Thus, molecular mediators of transcriptional processes represent important and exciting targets for new therapies and define a large number of the current translational projects in the group. Representative highlights of our recent work include:
The development of inhibitors of cyclin-dependent kinase 7 (CDK7). CDK7 has numerous roles within a cell including cell cycle regulation. CDK7 is also necessary for transcription, and acts by phosphorylating RNA polymerase II to enable transcription initiation. CDK7 additionally regulates the activities of a number of transcription factors, including estrogen receptor-α. We were previously involved in a large drug discovery team effort at Imperial College that took this project from a clinical hypothesis and virtual chemical scaffolds to a clinical drug candidate which is currently undergoing clinical trials in the UK. Representative publications: Mol. Cancer Ther. 2018, in press. DOI; ChemMedChem. 2017, 12, 372. DOI; Cancer Res. 2009, 69, 6208. DOI
Epigenetic targets. The human genome is packaged into chromatin, a macromolecular complex consisting of DNA, histone and non-histone proteins. Chromatin structure and signalling plays a critically important role in transcriptional regulation via so-called epigenetic processes. Histone post-translational modifications (including acetylation, methylation, phosphorylation, etc) are key mediators in epigenetic transcriptional control and thus the proteins responsible for the regulation of these epigenetic ‘marks’ represent interesting drug targets. Representative ongoing projects include:
The histone lysine methyltransferases (HKMT) as drug targets.
(i) Cancer. HKMTs are enzymes that transfer one or more methyl groups to specific lysine residues on histone (and non-histone) proteins. Many cancers show dependencies on the histone methyltransferases to maintain an aberrant epigenetic state. Together with Professor Bob Brown, we have found that dual pharmacological inhibition of the repressive HKMTs EHMT2 and EZH2 has greater activity than selective inhibition of either enzyme. We have identified dual EHMT2/EZH2 inhibitors and continue to explore the application of these proof of concept compounds in a range of cancer subtypes/therapeutic combinations. Representative publication: Clin. Epigenetics 2015, 7:84 DOI.
(ii) Malaria. Together with Professor Artur Scherf we were the first to discover Plasmodium histone methyltransferase (PfHKMT) inhibitors that result in blood stage independent parasite killing. In collaboration with Prof. Dominique Mazier we also discovered our inhibitors to have the unprecedented ability to ‘reawaken’ dormant liver stage parasites. Dormant and largely drug resistant Plasmodium parasites (in P.vivax) cause recurrent malaria and are a significant and largely untreatable clinical problem; this drug induced ‘awakening’ approach holds much hope to tackle such a limitation and therefore provide a new therapeutic option for this disease. Representative publications: MedChemComm 2017, 8, 1069. DOI; Nature Med. 2014, 20, 307. DOI; P. Natl. Acad. Sci. USA 2012, 109, 16708. DOI.
The histone deacetylases (HDACs) as drug targets.
HDACs are enzymes that remove acetyl (and sometimes longer chain acyl) groups from specific lysine residues on histone (and non-histone) proteins. We have worked on the development of inhibitors against the two mechanistically distinct classes of HDAC enzyme: the metallo-HDACs and the NAD+-dependent sirtuins. Sirtuin 2 (SIRT2) is a Class III (NAD+-dependent) HDAC and has been a particular recent focus. SIRT2 is involved in a number of cellular processes including histone and tubulin deacetylation. This target has been implicated in a number of age related disorders, including cancer. Furthermore, genetic or pharmacological knockdown of SIRT2 function is protective in both Parkinson’s and Huntingdon’s disease models. In collaboration with Professor Eric Lam, Professor Mike Sternberg and Professor David Dexter, we continue to study the role of SIRT2 in disease, through the development and application of unique chemical tools. For example, we have discovered a structurally novel SIRT2 inhibitor chemotype, with an excellent SIRT2 selectivity profile, which has a protective effect in Parkinson’s disease cellular models. Representative publications: J. Med. Chem. 2017, 60, 1928. DOI; ChemMedChem 2015, 10, 69. DOI; Mol. Cancer Ther. 2010, 9, 844. DOI.
Other transcriptional targets. We continue to develop therapeutic approaches via the targeting of other transcriptional regulatory proteins. In collaboration with Professor Hugh Brady, we are pursuing a transcription regulator that we have shown to be critical to the development of natural killer (NK) cells. NK cells are critical immune effector cells and the adoptive transfer of large numbers of cytolytic NK cells represents a developing cancer immunotherapeutic approach. We have identified inhibitors that massively enhance the production of NK cells and thus represents a potential opportunity of improved cancer immunotherapy via NK cells.
Other ongoing projects
Outside of our core interests in the development of therapeutic approaches towards transcriptional targets, we are working on a range of other collaborative and translational projects, which leverage the strong biological research at Imperial and its partner institutes (Crick, MRC LMS, etc.). These projects span a range of target classes – kinases, DNA processing and repair proteins, motor proteins – and a range of diseases – cancer, infectious diseases (malaria, antibiotics, antifungals), cardiovascular disease, neurological diseases, etc. In addition, we continue to seek interesting ways to couple our medicinal chemistry endeavours to broader therapeutic approaches. For example, in collaboration with scientists at CSIRO, we have been developing polymeric delivery systems that link a delivery hypothesis to the medicinal chemistry of a particular target of interest in cancer. Representative publication: Polym. Chem. 2018, 9, 131. DOI.
Where required, we are applying chemical biological target validation approaches to inhibitors developed in our medicinal chemistry efforts. For example, we have recently published the design and development of a small-molecule photo-cross-linkable probe to investigate the targets of our diaminoquinazoline series of PfHKMT inhibitors. We have demonstrated the effectiveness of our designed probe for photoaffinity labelling of Plasmodium lysates and continue to use these tools in ongoing target validation studies. Representative publication: ACS Infect. Dis. 2018, in press. DOI.
Coupled with our interest in therapeutics of transcriptional pathways, we have a number of on-going (unpublished) projects, particularly in collaboration with Dr Pete DiMaggio, surrounding the development of chemical biological tools that would enable better biological understanding of epigenetic events. These include a novel technology to map the ‘methylome’ maintained by specific histone lysine methyltransferases (HKMTs) and a unique chemical means to map specific histone marks. We are also developing novel epigenetic imaging agents and other tool reagents to facilitate our studies aimed at validating these important targets in disease.
Photopharmacology is a rapidly growing approach that uses light to change the shape and/or properties of a therapeutic agent. Such photoswitching, in turn, changes the biological activity of the compound. Therefore, in its most simple form, photopharmacology is an approach to switch the activity of a drug ‘on’ and ‘off’ using light. Coupling our work on novel photoswitchable molecules to our interests in medicinal chemistry and chemical biology, we have a number of ongoing collaborative projects aimed at the generation of photopharmacological agents. For example, we have recently published the development of a photopharmacological antimicrobial agent in collaboration with Professor Franz-Josef Meyer-Almes. Amidohydrolase enzymes homologous to the well-known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital-acquired infections and deaths. We have reported photopharmacological inhibitors of these enzymes, showing our arylazopyrazole photoswitches to exhibit better intrinsic photoswitch performance to the more commonly used azobenzenes when incorporated into the inhibitor design. We have also reported protein–ligand crystal structures of these compounds bound to bacterial histone deacetylase-like amidohydrolases (HDAHs) which, in part, rationalise the selectivity data obtained. As such, our data may pave the way for the design of improved photopharmacological agents targeting the HDAC superfamily. Representative publication: ACS Infect. Dis. 2017, 3, 152. DOI.