The Walter and Eliza Hall Institute of Medical Research

Dr Chris Burns

Details

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Division: Chemical Biology

Research Overview

The discovery of novel drugs that are safe, orally bioavailabile (i.e. can be taken as a pill) and that target discrete molecular processes driving cancer cell growth is now a major focus of research in both academic and commercial sectors. Such drugs have reduced side-effects and improved patient convenience compared to conventional cancer chemotherapeutics. Our laboratory’s research is focussed on the identification and optimisation of new chemical compounds that fulfil these criteria.

Principally we are concerned with the design and synthesis of new chemical matter for use as chemical tools to inform studies in cancer biology, with the ultimate aim of discovering novel anticancer therapeutics. This work integrates a number of different approaches from the fields of medicinal chemistry, chemical biology, and drug design and development:

• optimization of drug activity and other properties to allow for further preclinical, and ultimately clinical, investigation
• development of drug structure-activity relationships and the structural basis for a compound’s activity
• determination of specific aspects of a compound’s mechanism of action through techniques such as bio-orthogonal chemistry.

Previous work at Melbourne-based biotechnology company Cytopia Research Pty Ltd (now YM BioSciences Australia) has led to the discovery of two drugs currently undergoing clinical trials: CYT387, a potent and selective dual JAK1/JAK2 inhibitor for the treatment of myelofibrosis; and, CYT997, a novel orally active vascular disrupting agent currently being investigated in the brain cancer glioblastoma multiforme.

Research Interests

We currently have a number of early stage research projects.

• Design, synthesis and optimisation of inhibitors of TBK1 for the treatment of K-RAS mutant positive cancers, such as pancreatic cancer and certain lung and colon cancers, using structure-guided drug design principles
• Design, synthesis and optimisation of inhibitors of eIF4A, an RNA helicase involved in the initiation of protein translation. The project involves the synthesis of congeners and analogues of the natural products rocaglamide and silvestrol
• Design and synthesis of chemical probes for epigenetic targets
• Development of new chemical probes for parallel profiling of cellular effects of kinase inhibitors

Selected Publications

1. Monaghan KA, Khong T, Burns CJ, Spencer A. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia. 2011 Dec;25(12):1891-9 [PMID: 21788946]
2. Burns CJ, Wilks AF. c-FMS inhibitors: a patent review. Expert Opin Ther Pat. 21:147-65. 2011. [PMID: 21204725]
3. Tyner J W, Bumm T G, Deininger J, Wood L, Aichberger K J, Loriaux M M, Druker B J, Burns C J, Fantino E and Deininger M W. CYT387, a novel jak2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood 115:5232–5240, 2010 [PMID: 20385788]
4. Burns C J, Fantino E, Phillips I D, Su S, Malcontenti-Wilson C, Bukczynska P E, Harte M F, Joffe M, Kruszelnicki I, Wang B, Wang Y, Dilley R J, Wan S, Charman S A, Shackleford D M, Fida R and Wilks. A F. CYT997: a novel oral vascular disrupting agent with potent antitumour activity in vivo. Mol Cancer Ther. 8:3036–45, 2009 [PMID: 19887548]
5. Burns C J, Bourke D G, Andrau L, Bu X, Charman S A, Donohue A C, Fantino E, Farrugia M, Feutrill J T, Joffe M, Kling M R, Kurek M, Nero T L, Nguyen T, Palmer J T, Phillips I, Shackleford D M, Sikanyika H, Styles M, Su S, Treutlein H, Zeng J and Wilks A F. Phenylaminopyrimidines as inhibitors of JAK kinases (JAKs). Bioorg. Med. Chem. Lett. 19:5887–92, 2009 [PMID: 19762238]
6. Burns C J, Bu X, Harte M F, Joffe M, Sikanyika H, Su S, Tranberg C E, Wang Y, Shackleford D, Charman S A and Wilks A F. Discovery of CYT997: a structurally novel orally active microtubule targeting agent. Bioorg. Med. Chem. Lett. 19:4639–4642, 2009 [PMID: 19616947]
7. Pardanani A, Lasho T, Smith G, Burns C J, Fantino E and Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 23:1441–45, 2009 [PMID: 19295546]
8. Burns C J, Harte M F, Bu X, Fantino E, Giarrusso M, Joffe M, Kurek M, Legge F S, Razzino P, Su S, Treutlein H, Wan S, Zeng J and Wilks A F.. Discovery of 2-(α-Methylbenzylamino) Pyrazines as Potent Type II Inhibitors of FMS. Bioorg. Med. Chem. Lett. 19:1206–09, 2009 [PMID: 19128971]
9. Irvine KM, Burns CJ, Wilks AF, Su S, Hume DA, and Sweet M. A CSF-1 receptor kinase inhibitor targets effector functions and inhibits pro-inflammatory cytokine production from murine macrophage populations. Faseb J. 20:1921, 2006 [PMID: 16877523]
10. Lucet I S, Fantino E, Styles M, Bamert R, Patel O, Broughton S E, Walter M, Burns C J, Treutlein H, Wilks A F, and Rossjohn J. The structural basis of JAK kinase 2 inhibition by a potent and specific pan-JAK kinase inhibitor. Blood 107:176–83, 2006 [PMID: 16174768]

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Current Laboratory Members

Faculty Member: Chris Burns BSc(Hons) Melb PhD Melb

Group Leader (CTx CRC): Paul Stupple BA Oxon DPhil Oxon

Postdoctoral Fellow (CTx CRC): Jo Alcindor BSc(Hons) Hertfordshire PhD Cantab

Postdoctoral Fellow: Ryan Brady BSc(Hons) LaT PhD Melb

Postdoctoral Fellow (CTx CRC): Danny Ganame BSc(Hons) LaT PhD Melb

Postdoctoral Fellow (CTx CRC): Georgina Holloway BAppSc(Hons) RMIT PhD Melb

Postdoctoral Fellow (CTx CRC): Romina Lessene BSc(Hons) Melb PhD Melb

Postdoctoral Fellow (CTx CRC): George Nikolakopoulos BAppSc(Hons) QUT PhD Mon

Postdoctoral Fellow: Louisa Phillipson BSc Surrey PhD Reading

Postdoctoral Fellow: Pat Sharp BSc(Hons) ANU PhD ANU

Postgraduate Student: Duong Thuy Nhu BSc(Hons) LaT

Undergraduate Student: Manal Ali BMedChem LaT

Research Assistant (CTx CRC): Wilco Kersten BSc Netherlands

Research Assistant: Thao Nguyen BSc VUT

Research Assistant: Dana Stachurska-Buczek MSc Poland