Faculty of Medical and Health Sciences

Development of New Anticancer Drugs

One of the primary missions of our group, as it is with the Auckland Cancer Society Research Centre itself, is to facilitate the advance of new anticancer drugs to clinical trial. Drugs that bind to DNA have formed one particular focus of this project, which started many years ago with the drug amsacrine, which was developed in this centre and which subsequently entered worldwide use for the treatment of acute myeloid leukaemia. Subsequent research has covered a large range of DNA binding anticancer drugs, culminating in the DNA binding compound SN 28049, which exploits cellular transport mechanisms to concentrate in tumour tissue; this drug has the potential to enter clinical trial. We have also collaborated with the University School of Pharmacy on novel formulation approaches to minimise the clinical toxicity of the drug asulacrine. Our other recent work has focussed on inhibitors of the enzyme phosphoinositide 3-kinase, and of inhibitors of EGFR and Axl receptor tyrosine kinases. 

Some recent publications are shown below.

Chen YY, Finlay GJ, Kirker J, Marshall ES, Richardson E, Baguley BC. In vivo and in vitro assessment of the action of SN 28049, a benzonaphthyridine derivative targeting topoisomerase II, on the murine Colon 38 carcinoma. Invest New Drugs 2011; 29: 1504-1510.

Chen YY, Lukka P, Joseph WR, Finlay GJ, Paxton JW, McKeage MJ, Baguley BC. Selective cellular uptake and retention of SN 28049, a new DNA binding topoisomerase II-directed antitumor agent. Cancer Chemother Pharmacol 2014; 74:25-35.

Drummond CM, Finlay GJ, Broome L, Marshall EM, Richardson E, Baguley BC. Action of SN 28049, a new DNA binding topoisomerase II-directed drug: comparison with doxorubicin and etoposide. Invest New Drugs 2011; 29: 1102-1110.

Jamieson S, Flanagan J, Kolekar S,  Buchanan C, Kendall JD, Lee W, Rewcastle GW, Denny WA, Singh R,  Dickson J, Baguley BC, Shepherd PR. A drug targeting only p110α can block PI 3-kinase signalling and tumour growth in certain cell types. Biochem J 2011; 438: 53-62.

Kendall JD, Giddens A, Tsang T, Frédérick R, Flanagan JU, Rewcastle GW, Denny WA, Marshall ES, Baguley BC, Jamieson S, Lill CL, Lee W-J, Kolekar S, Chaussade C, Buchanan C, Shepherd PR.  Novel pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors: Exploring the benzenesulfonohydrazide SAR. Bioorg Med Chem 2012; 20: 58-68.

Kendall JD, Marshall AJ, Giddens AC, Boyd M, Frédérick R, Marshall ES, Lill CL, Lee WJ, Kolekar S, Chao M, Malik A, Yu S, Chaussade C, Buchanan C, Rewcastle GW, Baguley BC, Flanagan JU, Denny WA, Shepherd PR. Novel pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors: variation of the central linker group. Med Chem Comm 2014; 5: 41-46.

Kendall JD, O’Connor P, Marshall A, Frédérick R, Flanagan JU, Rewcastle GW, Denny WA, Marshall ES, Baguley BC, Jamieson S, Shepherd PR, Lill CL, Lee W-J, Kolekar S, Chaussade C, Buchanan C.  Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors Bioorg Med Chem 2012; 20: 69-85.

Lukka P, Chen YY, Finlay GJ, Joseph WR, Richardson E, Paxton JW, Baguley BC. Tumour tissue selectivity in the uptake of SN 28049, a new topoisomerase II-directed anticancer agent. Cancer Chemother Pharmacol 2013; 72: 1013-1022.

Lukka PB, Paxton JW, Kestell P, Baguley BC. Comparison of a homologous series of benzonaphthyridine anti-cancer agents in mice: divergence between tumour and plasma pharmacokinetics. Cancer Chemother Pharmacol 2012; 70; 151-160.

Rewcastle GW, Gamage SA, Flanagan JU, Kendall JD, Denny WA, Baguley BC, Buchanan CM, Chao M, Kestell P, Kolekar S, Lee W-J, Lill CL, Malik A, Singh R, Jamieson SMF, Shepherd PR. Synthesis and biological evaluation of novel phosphatidylinositol 3-kinase inhibitors: solubilized 4-substituted benzimidazole analogues of 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). Eur J Med Chem 2013; 64: 137-147.

Rewcastle GW, Marshall AJ, Lill CL, Chao M, Kolekar SV, Lee WJ, Marshall ES, Baguley BC, Shepherd PR, Denny WA, Flanagan JU.  Exploring the isoform selectivity of TGX-221 related pyrido[1,2-a]pyrimidinone-based Class-Ia PI 3-kinase inhibitors: synthesis, biological evaluation and molecular modelling. Bioorg Med Chem. 2015; in press.

See E, Zhang W, Liu J, Svirski C, Baguley BC, Shaw JP, Wang G, Wu Z. Physicochemical characterization of asulacrine towards the development of an anticancer liposomal formulation via active drug loading: stability, solubility, lipophilicity and ionization. Int J Pharmaceut 2014; 478: 528-535.

Sutherland HS. Lindsay BS, Denny WA, Hwang IY, Marshall ES, Greenhalgh D, Richardson E, Ding A, Baguley BC. Therapeutic reactivation of mutant p53 protein by quinazoline derivatives. Invest New Drugs 2012; 30: 2035-2045.