Thursday, 20 November 2014
Any scientist will tell you that collaboration is the key to success. For us here at AstraZeneca, this paradigm is particularly important to the way we work. In this blog post, I will give an update on one such collaboration – with the China-based research organisation, Pharmaron.
This partnership was established in June 2012, with the aim of delivering a significant amount of new drug discovery work. Pharmaron now works closely with our internal groups to deliver a wide variety of services in synthetic chemistry and in drug metabolism and pharmacokinetics (DMPK).
The partnership has given us greater flexibility to deal effectively with fluctuations in internal demand for this type of work. Pharmaron are very service-minded, and their scientists are willing to learn and adapt, which has made them excellent partners. Of course, there have been challenges along the way, for example with regard to communication and documentation, but these have now largely been overcome.
Importantly, the AstraZeneca and Pharmaron scientists work as one team. This demonstrates that – with commitment from both sides – external partnering in early-stage drug development can be successful, even across geographical boundaries.
Partnership in practice
How does the partnership operate in day-to-day working practice? A good example is Pharmaron’s involvement in our synthetic chemistry work – the synthesis of novel compounds that can then be used in drug development studies.
Typically, the design of new compounds is done internally, by specialists within AstraZeneca. In my own role as a computational chemist, I am often a part of this process, providing projects with various kinds of data analysis and 3D visualisation to aid the design of new compounds. Once molecules have been designed and ‘drawn out on paper’ by AstraZeneca, Pharmaron is engaged to help achieve the realisation of those designs into actual molecules (i.e. the chemical synthesis of the molecules).
The scientific exchange between synthetic chemists from AstraZeneca and Pharmaron has been positive. Some of the compounds that come from the AstraZeneca design table are difficult to synthesise, but information sharing and discussion help facilitate this process.
Watch the video to learn more about the collaboration between Pharmaron and AstraZeneca
GPR103 – a case in point
The Pharmaron collaboration has brought particularly tangible success with the so-called ‘GPR103 antagonists’. GPR103 is a receptor found in the cell membrane in certain areas of the brain, and has been linked with appetite-stimulating properties when activated by endogenous neuropeptides (Chartrel et al. 2003; Takayasu et al. 2006). Hence, it has potential as a therapeutic target for weight loss.
Working alongside Pharmaron, we have developed a group of synthetic compounds that appear to act as antagonists of GPR103. This work was recently published in Journal of Medicinal Chemistry (Georgsson et al. 2014).
The metabolism and pharmacokinetics of the lead compounds in this group suggest that they are suitable for drug development. Most importantly, the anorexigenic effect of one of these molecules has been demonstrated in a mouse obesity model. Put simply, this compound was able to reduce the food intake of mice (Georgsson et al. 2014). It is not yet known whether any of these synthetic compounds will have similar effects in humans, but our research is a valuable step towards understanding the biological role of GPR103.
In September at the EFMC-ISMC 2014 I presented some of our latest work on the effect of small GRP103 molecular probes in mice, where the GPR103A and B gene were removed one at the time, providing another piece of the puzzle in understanding the biological role of this receptor. Coming up in December our second collaborator on this paper, C4X Discovery, will present more details of the molecular modelling of our GPR103 antagonists and the use of peptide solution structures in drug discovery.
At AstraZeneca, we are particularly proud of the GPR103 research paper for two reasons:
- It is the first publication to result from our collaboration with Pharmaron and the importance of their role is acknowledged in our shared authorship of the paper. We are keen to continue to develop our existing early stage relationships whilst building new links, both with peers and within academia.
- The results open up new avenues for academic research. Although some excellent work had previously been done on the biological roles of GPR103, our paper has advanced the field significantly. It is very exciting to characterise new therapeutic targets, and to see their potential opened up to both industry and academia.
Building new and strong relationships with both industry partners and academic collaborators will remain a major priority for the future.
- Chartrel et al. (2003). Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. Proc Natl Acad Sci USA 100:15247-52.
- Georgsson et al. (2014). GPR103 antagonists demonstrating anorexigenic activity in vivo: design and development of pyrrolo[2,3-c]pyridines that mimic the C-terminal Arg-Phe motif of QRFP26. J Med Chem 57(14):5935-48.
- Takayasu et al. (2006). A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice. Proc Natl Acad Sci USA 103:7438-43.