Congratulations to CFBD Deputy Director A/Prof Ben Capuano for being appointed as Acting Theme Leader in the Medicinal Chemistry Department at the Monash Insitute of Pharmaceutical Sciences (MIPS).
Ben has taken over the position from Prof Peter Scammells who will now be focusing on his role as Associate Dean, Research, Faculty of Pharmacy & Pharmaceutical Sciences. Within CFBD, Ben leads the Fragment Elaboration theme. He is a synthetic medicinal chemist specialising in GPCRs.
Congratulations to CFBD CI Professor Jonathan Baell for being awarded the Faculty Research Award from the Monash Institute of Pharmaceutical Sciences.
Jonathan discovers new medicines for treating diseases with unmet medical needs with a particular focus on cancer and infectious diseases. His track record is hallmarked by high-quality research outcomes in a variety of different areas, as exemplified by a broad and diverse suite of personally driven but widely collaborative patents integrated with subsequent high-quality publications.
With more than 70 granted patents, throughout his career Jonathan has been a driving force in facilitating commercial outcomes from academic research. At any given time, he incubates a variety of enterprising projects to maximise the chances of multiple translational outputs.
He is also the Director of the Australian Translational Medicinal Chemistry Facility (ATMCF), located at MIPS and which works with researchers nationwide in order to translate biomedical research outcomes. The Facility has secured over $7M in funding to enable the de-risking of projects through medicinal chemistry optimisation. In addition to the enterprise embodied in the ATMCF, Jonathan’s own patented KAT6A anticancer drug candidates have catalysed a global focus by Pharma on KATs as druggable targets. This innovative KAT6A work also has underpinned several awards, including Australia’s highest medicinal chemistry award, the Adrien Albert Award for Sustained Excellence in Medicinal Chemistry (2018), the Monash University Research Award for the Faculty of Pharmacy and Pharmacology (2019), the Scientific Achievement Award in Drug Discovery and Development (2020), awarded by the American Society for Pharmacology and Experimental Therapeutics, and in 2021 The Australian Academy of Technology and Engineering (ATSE) Clunies Ross Award for Knowledge Commercialisation.
Congratulations to CFBD CI Professor Joel Mackay from Sydney University who received an NHMRC Ideas Grant worth $829, 494.
This project will pioneer the development of a new class of molecules – cyclic peptides – that will block the activity of proteins that regulate gene expression and have been shown to be promising targets for a range of diseases, predominantly cancer. These molecules have the potential to be much more selective and potent than existing molecules and to also open up new directions for cancer therapy by allowing previously intractable molecular targets to be addressed.
This one-day workshop is a joint event of the ARC CoE for Climate Extremes (CLEX), the ARC CoE for Mathematical & Statistical Frontiers (ACEMS) and the CFBD.
The Media and Presentation Training workshop will provide you with the skills to develop confidence during interviews with the media, the general public or job interviews. It is designed to help you develop the skills to get your message across. It will show you why everything you know about communications is wrong and give you the basics of communications: how to build your narrative, how to control the interview, how to deal with and master difficult questions. There will be hands-on group works together with delegates from CLEX and ACEMS and mock interviews to practice your skills.
Come and join us at Monash University‘s Faculty of Pharmacy and Pharmaceutical Sciences. We have 2 PhD scholarships available.
The strategy of FBDD involves screening libraries of small chemical compounds or ‘fragments’ that, owing to their size, generally bind with relatively low affinity and then elaborating these to produce larger, higher affinity ligands (or hits). The process of fragment elaboration to generate high-affinity compounds remains one of the major challenges in FBDD. Projects in the CFBD involve research in different aspects of this process and require expertise in one or more of the following areas: medicinal chemistry, structural biology, biophysics, and/or biochemistry.
Current projects involve the development of novel antibacterial and antiviral compounds; development of novel approaches to screening “difficult” targets; development of compounds for the treatment of metabolic disease.
Please visit Jobs at Monash for more information.
The ARC CFBD aims to advance the techniques and workflows of fragment-based drug design to establish new avenues for drug discovery. Our team have used our novel workflow called REFiL (Rapid Elaboration of Fragments into Leads) to demonstrate accelerated development of leads for drug discovery. This new method has the potential to produce a drastic reduction in cost for R&D, as well as expedite identification of potential drug leads.
Fragment-Based Drug Discovery (FBDD) is an established field of study where small drug building blocks of less than 20 non-hydrogen atoms (i.e. fragments) form the basis for lead-like compounds. Fragment-based leads are superior candidates for progressing through to drug development because they offer opportunities to incorporate better physical properties and, therefore, tackles the issue of late stage attrition that can occur in traditional drug discovery pipelines.
Despite these advantages, FBDD is not without its drawbacks. Elaboration of fragments into potent leads typically relies on structural data, usually in the form of X-ray crystallography, which is a costly bottleneck and limits the type of protein targets to those that readily crystallise. Generation of various elaborated compounds to test for potency is also inherently expensive and time-consuming – rendered more laborious by the need for compound purification. Unfortunately, it is often the case that these elaborated compounds achieve meagre affinity gains that fail to justify the cost of consumables for synthesis or purification.
Our REFiL workflow aimed to address these hurdles. First, our program of analogue design leverages chemical diversity in lieu of structural data to guide compound generation. Second, this chemistry is performed in parallel, on microscale and in a plate-based format using curated reagent libraries, making this highly cost- and time-efficient. These elaborated libraries can then be assessed unpurified using Off-Rate Screening by SPR. This ability to generate huge amounts of chemical matter which could be assessed unpurified drastically expedited this traditionally laborious process. The workflow boasts an impressive 100-fold affinity improvement in the space of under a year to achieve lead-like compounds.
Published on ChemRxiv, the team applied the REFiL workflow to develop lead-like compounds for the extra terminal domain of bromodomain-3 (BRD3-ET), a target for cancer therapeutics. Bromodomain containing proteins are key regulators of transcription in the cell cycle, and the oncological potential of these proteins is well established.
The application of REFiL to BRD-3ET led to three promising analogues for further development into lead-like compounds. On a target specific level, this represents a huge step in the fields of oncology and epigenetics as the role of the extra terminal domain is poorly elucidated. Designing lead-like compounds for BRD-3ET will help illuminate the holistic function of this protein in transcriptional activity.
The impact of this workflow has widespread application potential throughout the pharmaceutical industry. It could see a reduction in R&D costs from failed early stage candidates. More topically, the cheap and expedited nature of lead generation by REFiL is sorely needed in tackling COVID-19 and other poorly understood diseases. We stand to greatly fine-tune our understanding of disease with the generalised application of this workflow.
Rapid elaboration of fragments into leads applied to Bromodomain-3 extra terminal domain
Adams, L. A.; Wilkinson-White, L. E.; Gunzburg, M. J.; Headey, S. J.; Scanlon, M. J.; Capuano, B.; Mackay, J. P.; Doak, B. C.
Dr Anitha Kopinathan was awarded an Early Career Researcher Grant by The Australian Institute of Nuclear Science and Engineering (AINSE).
AINSE boosts the capability of Australia and New Zealand in nuclear science, engineering and related research field by facilitating collaboration, education and training. The Early Career Researcher Grant provides a single payment of A$10,000 to contribute to expenses in travel, accommodation, consumables and carer requirements for the recipient.
Dr Kopinathan’s Early Career Researcher Grant will support her collaborative research with Australia’s Nuclear Science and Technology Organisation. She will synthesise 19F-13C labelled amino acid probes for the investigation of protein structure and dynamics by NMR spectroscopy. Incorporation of isotopically labelled amino acids into proteins improves the resolution of NMR signals, allowing larger biomolecular systems to be investigated.
Her work will benefit the research efforts of ARC CFBD in furthering our understanding of protein dynamics, ligand binding and the interplay between the two.
Dr Narelle Tunstall, Centre Manager
The Centre for Fragment-Based Design officially commenced on 22 July 2019 with the execution of our Participants Agreement and the Centre was launched by The Honourable Kevin Andrews MP on 12 November 2019. The launch was held in conjunction with Australia’s national conference on Fragment-Based Drug Design, which allowed us to leverage a full week of activities including our first Scientific Advisory Board meeting and the Centre’s first training events, in partnership with key industry and international stakeholders.
The launch, conference and training workshops were very well received by attendees, with many of our academic and industry participants and other stakeholders in attendance. These initial activities have established a strong base of interest in the Centre for further collaborative opportunities that will drive our research initiatives and support growth, productivity and competitiveness in fragment-based design for the sector.
There was some great coverage of the event. Monash and Griffith both had media releases publicising the launch event, which were picked up by a Universities to Business article.
Our partners GE Healthcare (now Cytiva) had a number of representatives, including Paul Belcher all the way from Boston, who wrote a great LinkedIn article about the event.
Dan Erlanson wrote a great summary article on his Practical Fragments blog.
Our objective to establish a coherent and collaborative national network to provide access to the technology necessary to support fragment screening against a wide range of protein targets, has now been firmly grounded in the established Centre. We now have a strong platform and clear means to implement our training program activities, accelerate research translation and continue to engage with industry to meet the growing needs within the rapidly moving sector.
Feature image: Centre CIs (L-R: Professor Jonathan Baell, Professor Sally-Ann Poulsen, Professor Michael Kassiou, Professor Joel Mackay, Dr Maria Halili, Professor Martin Scanlon and Professor Ray Norton) with ARC CEO Professor Sue Thomas and Centre Manager Dr Narelle Tunstall.
ARC Centre for Fragment-Based Design 