Our laboratory focuses on chemical biology approaches at a basic research level to identify and understand new biological mechanisms. We also concentrate on harnessing medicinal chemistry methods to target biological processes with the aim to develop new small molecules therapeutics.
We have strong collaborations with researchers both within our institute and externally, across a variety of disciplines, including:
– high throughput screening
– structural biology
Our team works closely with industry partners in several drug discovery programs dedicated to developing new therapeutics in the cancer and infectious disease fields.
Our laboratory has interests in:
– Design of small molecule inhibitors of aspartyl proteases to understand their role in the malaria and cryptosporidiosis.
– Design of small molecules to target SH2 domain proteins to investigate their role in inflammation and cancer.
– Identification of the mechanism of action of small molecule antimalarials currently under optimisation in our laboratory.
– Development of small molecule therapies to treat human and animal helminthiasis.
Australia, La Trobe University, BSc Hons, 1999
Australia, La Trobe University, PhD, 2005
Honorary Senior Fellow, Department of Medical Biology, University of Melbourne,
Honorary Principal Fellow, Department of Veterinary Biosciences, University of Melbourne
2020 RACI MCCB Division, Peter Andrews Award for Innovation in Medicinal Chemistry
2020 Royal Australian Chemical Institute Fellow
2019 Max O’Connor Lectureship, La Trobe University
2016 Australian Infectious Diseases Research Centre Eureka Prize Finalist, Museum Australia
2022-2024 Development Grant, NHMRC
2021-2023 Ideas Grant, NHMRC
2021-2023 Linkage Grant, ARC
2020-2022 Innovation Grant, Wellcome Trust
2018-2023 Ellen Corin Centenary Fellowship in Cancer Therapeutics, Walter and Eliza Hall Institute
2018-2019 Seeding Drug Discovery Grant, Wellcome Trust
Ashton, T. D.; Dans, M.G.; Favuzza, P.; Ngo, A.; Lehane, A. M.; Zhang, X.; Qiu, D.; Chandra Maity, B.; De, N.; Schindler, K.A.; Yeo, T.; Park, H.; Uhleman, A.-C.; Churchyard, A.; Baum, J.; Fidock, D.A.; Jarman, K.E.; Lowes, K. N.; Baud, D.; Brand, S.; Jackson, P. F.; Cowman, A. F.; Sleebs, B. E. Optimization of 2,3-dihydroquinazoline-3-carboxamides as antimalarials targeting PfATP4. J. Med. Chem. 2023, PMID: 36812492
Nguyen, W.; Dans, M. G.; Currie, I.; Awalt, J. K.; Bailey, B. L.; Lumb, C.; Ngo, A.; Favuzza, P.; Palandri, J.; Ramesh, S.; Penington, J. S.; Jarman, K. E.; Mukherjee, P.; Chakraborty, A.; Maier, A. G.; van Dooren, G. G.; Papenfuss, T.; Wittlin, S.; Churchyard, A.; Baum, J.; Winzeler, E.A.; Baud, D.; Brand, S.; Jackson, P. F.; Cowman, A. F.; Sleebs, B. E. ACS Infect. Dis. 2023, PMID: 36853190
Chen H.; Nguyen, N.; Magtoto, C; Cobbold, S.; Richardson, L. W.; Meza, L.; Au, A.; Corbin, J.; Lechtenberg, B.; Sutherland, K.; Feltham, B.; Grohmann, C.; Nicholson, S. N.; Sleebs, B. E. Design and characterization of a heterobifunctional degrader of KEAP1. Redox. Biol. 2023, 59, 102552. PMID: 36473314
Chen H.; Li, K.; Wu, Y.; Currie, I.; Keating, N.; Dehkhoda, F.; Grohmann, C.; Babon, J. J.; Nicholson, S. N.; Sleebs, B. E. Optimization of phosphotyrosine peptides that bind to the SH2 domain of SOCS1 and block substrate ubiquitination. ACS Chem. Biol. 2022, 17(2), 449–462. PMID: 34989544
Nguyen, W.; Dans, M. G.; Ngo, A.; Gancheva, M. R.; Romeo, O.; Duffy, S.; de Koning-Ward, T. F.; Lowes, K. N.; Jousset Sabroux, H.; Avery, V. M.; Wilson, D. W.; Gilson, P.R.; Sleebs, B.E. Structure activity refinement of phenylsulfonyl piperazines as antimalarials that block erythrocytic invasion. Eur. J. Med. Chem. 2021, 214, 113253. PMID: 33610028
Nguyen, W.; Lee, E. F.; Evangelista, M.; Lee, M.; Harris, T. J.; Colman, P. M.; Williams, L. B.; Smith, N.; Lowes, K. N.; Haeberli, C.; Keiser, J.; Smith, B. J.; Fairlie, D. W. Sleebs, B. E. Optimization of benzothiazole and thiazole hydrazones as inhibitors of schistosome BCL-2. ACS Infect. Dis. 2021, 7(5) 1143-1163. PMID: 33523649
Currie, I.; Sleebs, B. E. Synthesis of acyl phosphoramidates via a modified Staudinger reaction. Org. Lett. 2021, 23(2) 464-468. PMID: 33379864
Chen H.; Mao R.; Brzozowski, M; Nguyen, N.; Sleebs, B. E. Late stage phosphotyrosine mimetic functionalization of peptides employing a nickel-catalyzed photoredox cross-coupling. Org. Lett. 2021, 23, 11, 4244-4249. PMID: 34029466
Bailey, B. L.; Nguyen, W.; Ngo, A.; Goodman, C. D.; Gancheva, M. R.; Favuzza, P.; Sanz, L. M.; Gamo, F-J.; Lowes, K. N.; McFadden, G. I.; Wilson, D. W.; Laleu, B.; Brand S.; Jackson, P. F.; Cowman, A. F.; Sleebs, B. E. Optimization of 2-(N-phenyl carboxamide) triazolopyrimidine antimalarials with moderate to slow acting erythrocytic stage activity. Bioorg. Chem. 2021, 115, 105244. PMID: 34452759
Nguyen, W.; Jacobson, J.; Jarman, K. E.; Blackmore, T. R.; Jousset Sabroux, H.; Lewin, S. R.; Purcell, D. F.; Sleebs, B. E. Optimization of 5-substituted thiazolyl ureas and 6-substituted imidazolopyridines as potential HIV-1 latency reversing agents. Eur. J. Med. Chem. 2020, 195, 112254. PMID: 32109369
Malaria is a devastating disease that results in 460,000 deaths annually. Our laboratory is contributing to the global effort to develop novel small molecule therapies to treat and eliminate malaria.
Our team is currently optimising several small molecule classes identified from phenotypic screening of the malaria parasite. The antimalarial classes exert differential activity against multiple stages of the parasite’s lifecycle and therefore have potential as a prophylactic, a curative therapy or being used to eliminate malaria from endemic regions.
We are also employing chemical biology and genetic techniques to identify the mechanism of action of the small molecule classes under development.
Team members: Trent Ashton, William Nguyen, Madeline Dans, Kyle Awalt, Wenyin Su, Petar Calic, Mahta Mansouri.
Collaborators: Alan Cowman, Kym Lowes, external collaborators and industry partners
The malaria parasite encodes ten cathepsin D-like and one viral aspartyl protease. Our laboratory is focused on developing small molecule tools and developing genetic models to help understand the essential role of these aspartyl proteases in malaria parasite survival. This research has established the essentiality of several malaria aspartyl proteases and therefore suggesting these are attractive antimalarial drug targets.
In the next phase of our research, we have identified drug-like starting points independently targeting several essential aspartyl proteases of the malaria and the closely related cryptosporidium parasite. Our team is currently developing these small molecule classes as potential therapeutics to treat malaria and cryptosporidiosis.
Team members: William Nguyen, Madeline Dans, Wenyin Su
Collaborators: Alan Cowman, Chris Tonkin, Kym Lowes and an industry partner
Natural killer (NK) cells have emerged as a potential target in the innate immune system as they are highly toxic to tumor cells.
Interleukin 15 (IL-15) is an essential regulator and activator of NK cells. Our institute has discovered a novel checkpoint protein, CIS (cytokine-inducible SH2-containing protein), enhances NK cell response to IL-15 and thus NK cell activity. CIS is a member of the Suppressor of Cytokine Signaling (SOCS) family and negatively regulates IL-15-mediated NK cell proliferation, and therefore inhibiting CIS is a strategy to activate NK cell populations to destroy tumor cells. Our team is currently developing small molecule inhibitors of CIS as a potential immune-oncotherapy.
Team members: Nghi Nguyen, Iain Currie, Lydia Scott, Sayali Shah, Petar Calic, Mahta Mansouri.
Collaborators: Sandra Nicholson, Jeff Babon, Nadia Kershaw, Kym Lowes and an industry partner
Parasitic worms (helminths) infect 50% of the human population and represent a major socioeconomic burden i due to the helminthiases that they cause in agriculture. Treatment failures and evidence of anthelmintic resistance are limiting treatment options, such that there is an unmet need for new treatment strategies.
Using molecular techniques and high throughout put screening, we have identified multiple small molecule classes with nematicide activity. Our aim is to use medicinal chemistry methods to optimise potency of these small molecules to achieve improve efficacy against nematode worms in vitro and ultimately in mouse models. A secondary aim is to use genomic and proteomic methods to understand the mechanism by which the small molecules under development kill nematodes.
Team members: Nghi Nguyen, Harrison Shanley
Collaborators: External collaborators and a industry partner