Hon Assoc. Prof. Laurence Wakelin

Laurence Patrick George Wakelin

BSc(Hons) University of Kent, UK, PhD Clare College, University of Cambridge, UK, FRSC, MRACI
Honorary Associate Professor
Email: l.wakelin@unsw.edu.au

BIOGRAPHICAL DETAILS

BSc(Hons) Chemistry, University of Kent, UK, 1971. PhD Pharmacology, Clare College, University of Cambridge, UK, 1975. Department of Pharmacology, University of Cambridge, Science Research Council Fellow 1975-1977, Medical Research Council Fellow, 1978-1980. Senior Scientist, Peter MacCallum Cancer Institute, Melbourne, 1981-1989. Professor of Cancer Research, University College Dublin, 1990-1997. Visiting Fellow, School of Chemistry, UNSW, 1998. Associate Professor, School of Medical Sciences, UNSW, 1999-2019. Appointed Honorary Associate Professor, School of Chemistry, UNSW, April 2019. 

SOCIETIES

Fellow Royal Society of Chemistry.  Member Royal Australian Chemical Institute. Member Australasian Society for Clinical and Experimental Pharmacology and Toxicology. Member AusBiotech. 

RESEARCH INTERESTS

Cancer is a disease that kills one in three of us. Practically all cytotoxic cancer drugs inhibit the biochemical functions of DNA, many doing so by binding to DNA directly. Our current research focusses on the discovery of novel DNA-targeted alkylating agents for the treatment of the brain tumour glioblastoma. This is a particularly lethal cancer, in large part, because the tumour is shielded from drugs in the circulation by the blood brain barrier (BBB). The BBB puts stringent restrictions on the physical properties of drugs that can access the brain by diffusion. For example, molecular weight must be less than 500 Daltons, lipophilicity should have a log P of about 2.5, the polar surface area should be less than 90 A sq, and the drug should be weakly basic. 

We are developing agents which accord with these requirements, that are intended to kill glioblastoma cells by inhibiting DNA replication as a result of crosslinking their DNA strands. In addition, the agents are designed to crosslink DNA in novel ways that cells will find difficult to repair. This is a collaborative effort involving the School of Chemistry, the Auckland Cancer Society Research Centre, and colleagues at University College London, and the University of Southampton. Here, in the School of Chemistry, the work involves ligand design by molecular modelling facilitated by docking and molecular dynamics; organic synthesis; and mass spectrometry, NMR, and spectrophotometric studies of ligand binding to DNA. Cytotoxicity and antitumour activity is evaluated by colleagues in Auckland, sequence selectivity, mechanisms of crosslinking and repair, and crystal structures of DNA-drug complexes are investigated by colleagues in the UK.

SELECTED PUBLICATIONS

  • Campbell, A.P., Wakelin, L.P.G., Denny, W.A., and Finch, A. M. Homobivalent conjugation increases the allosteric effect of 9-aminoacridine at the α1 adrenergic receptors. Molecular Pharmacology (2017) 91, 135-144. DOI: 10.1124/mol.116.105874 Epub 2016 Nov 30.
  • Drwal, M.N., Marinello, J., Manzo, S., Wakelin, L.P.G., Capranico, G., and Griffith, R. Novel DNA topoisomerase IIα inhibitors from combined ligand- and structure-based virtual screening. PLoS ONE (2014) Dec 9; 9(12):e114904. DOI: 10.1371/journal.pone.0114904.
  • Serobian, A., Thomas, D., Ball, G., Denny, W.A., and Wakelin, L.P.G. The solution structure of bis(phenazine-1-carboxamide)-DNA complexes: MLN 944 revisited and extended. Biopolymers (2014) 101: 1099-1113. DOI:10.1002/bip.22513
  • Drwal, M.N., Agama, K.K., Wakelin, L.P.G., Pommier, Y., and Griffith, R. Exploring DNA Topoisomerase I Ligand Space in Search of Novel Anticancer Agents. PLoS ONE (2011) 6(9): e25150. doi: 10.1371/journal.pone.0025150.
  • Zihlif, M., Catchpoole, D.R., Stewart, B.W., and Wakelin, L.P.G. Effects of DNA minor groove binding agents on global gene expression. Cancer Genomics and Proteomics (2010) 7: 323-330.
  • Abdul Majid, A.M.S., Smythe, G., Denny, W.A. and Wakelin, L.P.G. Mass spectrometry studies of the binding of the minor groove-directed alkylating agent alkamin to AT-tract oligonucleotides. Chemical Research in Toxicology (2009) 22: 146-157. DOI: 10.1021/tx800276h.
  • He, Z., Bu, X., Eleftheriou, A., Zihlif, M., Qing, Z., Stewart, B.W., and Wakelin, L.P.G.. DNA threading bis(9-aminoacridine-4-carboxamides): effects of piperidine sidechains on DNA binding, cytotoxicity and cell cycle arrest. Bioorganic Medicinal Chemistry (2008) 16: 4390-4400. DOI:10.1016/j.bmc.2008.02.063
  • Abdul Majid, A.M.S., Smythe, G., Denny, W.A. and Wakelin, L.P.G. Structure of the d(CGCGAATTCGCG)2 complex of the minor grove binding alkylating agent alkamin studied by mass spectrometry. Molecular Pharmacology (2007) 71: 1165-1178. DOI: 10.1124/mol.106.030072.
  • Edwards, G.L., Black, St.C., D., Deacon, G.B. and Wakelin, L.P.G. Effect of charge and surface area on the cytotoxic activity of cationic metallointercalation reagents. Canadian Journal Chemistry (2005) 83: 969-979.
  • Wakelin, L.P.G., Bu, X., Eleftheriou, A., Parmar, A., Hayek, C., Stewart, B.W. Bisintercalating threading diacridines: relationships between DNA binding, cytotoxicity and cell cycle arrest. Journal Medicinal Chemistry (2003) 46: 5790-5802. DOI: 10.1021/jm030253d
  • Adams A, Guss JM, Denny WA, Wakelin LP. Crystal structure of 9-amino-N-[2-(4-morpholinyl)ethyl]-4-acridinecarboxamide bound to d(CGTACG)2: implications for structure-activity relationships of acridinecarboxamide topoisomerase poisons. Nucleic Acids Research (2002) 30:719-25.
  • Adams, A., Collyer, C., Guss, M., Denny, W.A. and Wakelin, L.P.G. Crystal structure of the topoisomerase II poison 9-amino-[N-(2-dimethylamino)ethyl]acridine-4-carboxamide bound to the DNA hexanucleotide d(CGTACG)2. Biochemistry (1999) 38: 9221-9233. DOI:10.1021/bi990352m

Current Research Students:

Mr. Christopher Pracey (Joint supervisor with Associate Professor Graham Ball).
Ms. Jane Jung (Joint supervisor with Dr. Luke Hunter and Associate Professor Graham Ball).
Ms. Grace Constable (Joint supervisor with Dr. Luke Hunter & Associate Professor Ball).
Mr. Adib Mohaimin (Joint supervisor with Dr. Luke Hunter and Associate Professor Ball).
Mr. Daniel Weissberger (Joint supervisor with Dr. Luke Hunter, Associate Professor Ball and Professor Martina Stenzel).

Current Major Collaborators

Associate Professor Graham Ball, School of Chemistry, UNSW.
Dr. Luke Hunter, School of Chemistry, UNSW.
Professor Martina Stenzel, School of Chemistry, UNSW.
Dr. Donald Thomas, School of Chemistry, UNSW.
Professor William A. Denny, Auckland Cancer Society Research Centre, New Zealand.
Professor Bruce Baguley, Auckland Cancer Society Research Centre, New Zealand.
Dr. Euphemia Leung, Auckland Cancer Society Research Centre, New Zealand.
Professor John Hartley, University College London.
Professor Stephen Neidle, University College London.
Associate Professor Gary Parkinson, University College London.
Professor Keith Fox, University of Southampton.