Associate Professor Laurence Wakelin

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 tumours glioblastoma (GB) and cranial metastatic triple negative breast cancer (TNBC). These are particularly lethal cancers, 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 Å sq, and the drug should be weakly basic. We are developing agents which accord with these requirements, that are intended to kill GB and cranial TNBC cancer cells by inhibiting DNA replication as a result of crosslinking their DNA strands 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 are 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.

Current Major Collaborators

Associate Professor Graham Ball, School of Chemistry, UNSW.
Associate Professor 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.
Associate Professor Gary Parkinson, University College London.
Professor Keith Fox, University of Southampton.