Combinatorial chemistry and molecular design

It takes 13 years and billions of dollars to get a drug to market. It is a difficult thing to do. You have to be prepared to fail, and you have to start from an excellent foundation.

You have to start with the right molecule. To get my attention, molecules must have a biological target within a mechanistic disease pathway. A mechanistic disease pathway is a step-by-step process impacting on the disease state. The molecule must be capable of blocking or activating that pathway with a favourable response.

Then I ask if we can block or activate this pathway, who cares? Will it be good for the patient and benefit society? And if so, will it be commercially viable?

We optimise the chemistry to probe these questions. Starting in the test tube, we then move on to a cell, an animal and then into the clinic.

I don’t want to fail because of what I don’t know. If I’m going to ask people to invest in a question, then I do everything I can to answer the hypothesis.

We are is currently working on a drug to block the initial inflammatory event that sets off an asthma attack.

We are also developing a new drug for Inflammatory Bowel Disease that can be taken orally and is more targeted than existing treatments.

Research title: Drug Discovery and Development

Summary of research interests: We work on developing new drug candidates to treat diseases that have significant unmet medical need. This includes both applied research, the discovery and development of drug candidates at specific disease targets, and basic research, the development of new methods and tools to facilitate the drug discovery process. Research outcomes are typically commercialised in spin-out companies, with numerous discoveries successfully translated to the clinic and in late-stage preclinical development. We have strong linkages to clinicians and the pharmaceutical industry. Projects are offered in the disciplines of drug design, mathematics, chemistry and biology, as related to the development of drugs for specific therapeutic targets.

Traineeships, honours and PhD projects include

• Optimisation of drug candidates for treatment of asthma
• Optimisation of drug candidates for treatment of breast cancer
• Synthesizing new chemical probes to unravel biological pathways
• Expanding constrained peptide evolution strategies to facilitate drug discovery
• Antibodies with teeth, a new therapeutic modality.

• Journal Article: Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23

  Barkan, David T., Cheng, Xiao-Li, Celino, Herodion, Tran, Tran T., Bhandari, Ashok, Craik, Charles S., Sali, Andrej and Smythe, Mark L. (2016) Clustering of disulfide-rich peptides provides scaffolds for hit discovery by phage display: application to interleukin-23. BMC Bioinformatics, 17 481: . doi:10.1186/s12859-016-1350-9

• Journal Article: Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo

  Ranganath, Sheila, Bhandari, Ashok, Avitahl-Curtis, Nicole, McMahon, Jaimee, Wachtel, Derek, Zhang, Jenny, Leitheiser, Christopher, Bernier, Sylvie G., Liu, Guang, Tran, Tran T., Celino, Herodion, Tobin, Jenny, Jung, Joon, Zhao, Hong, Glen, Katie E., Graul, Chris, Griffin, Aliesha, Schairer, Wayne C., Higgins, Carolyn, Reza, Tammi L., Mowe, Eva, Rivers, Sam, Scott, Sonya, Monreal, Alex, Shea, Courtney, Bourne, Greg, Coons, Casey, Smith, Adaline, Tang, Kim, Mandyam, Ramya A., Masferrer, Jaime, Liu, David, Patel, Dinesh V., Fretzen, Angelika, Murphy, Craig A., Milne, G. Todd, Smythe, Mark L. and Carlson, Kenneth E. (2015) Discovery and characterization of a potent interleukin-6 binding peptide with neutralizing activity in vivo. PLoS One, 10 11: 1-19. doi:10.1371/journal.pone.0141330

• Journal Article: Conformational searching using a population-based incremental learning algorithm

  Long, Stephen M., Tran, Tran T., Adams, Peter, Darwen, Paul and Smythe, M. L. (2011) Conformational searching using a population-based incremental learning algorithm. Journal of Computational Chemistry, 32 8: 1541-1549. doi:10.1002/jcc.21732

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We are a commercially focussed research group translating academic discoveries into start-up companies and license deals with the pharmaceutical sector. Some of these commercial enterprises have raised > AU$170M in commercial funding and resulted in licensing compounds for valuations exceeding AU$1B.

Our projects are multidisciplinary and focus on achieving medical outcomes. Several of them involve partnerships with industry. They range from technology development and early drug discovery to Investigational New Drug enablement. Using a combination of mathematics, software development, drug design, medicinal chemistry, pharmacology, structural biology and phage display, we are developing new approaches to treat diseases with unmet medical need. We have active late-stage preclinical programs in diverse therapeutic areas such as asthma, pain, iron overload disorders, and inflammatory bowel disease. 

We collaborate widely with clinicians and researchers on the application our chemical methods to relevant biology underpinning disease. Associate Professor Simon Phipps heads the respiratory neuroscience and mucosal immunity laboratory at the University of Queensland and has world-leading models of Asthma. Associate Professor Kiarash Khosrotehrani is a clinical scientist interested in skin biology, regenerative medicine and skin cancer at the University of Queensland. Kiarash has validated animal models of hair loss.  Professor Garland Marshall is Professor of Biochemistry & Molecular Biophysics and of Biomedical Engineering at Washington University and has broad research interests in molecular recognition with a focus on experimentally determining precise intermolecular distances in biomolecular complexes using modern pulse EPR spectrometers.