BMC Seminar, Wednesday, 13th May at 12:20, Room 343, Læknagarður

Speaker: Dr. Jóhannes Reynisson, Senior Researcher, School of Chemical Sciences, University of Auckland, New Zealand

Title: Development of thienopyridines as anticancer agents

Short abstract: The phosphoinositide specific-phospholipase C – γ enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells [1]. Virtual high throughput screening was performed against this target and the hit compounds tested in a biochemical and cell based assays [2]. The most active compounds were in the single digit micro-molar range, which translated into ~15 M for the most active compound in functional assays in cells [2]. These compounds were tested against the National Cancer Institute’s human tumour cell line panel (NCI60) panel of human tumour cell lines [3]. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 1 (see figures) giving GI50 = 58 nM for the melanoma MDA-MB-435 cell line [4]. The biological effect was further investigated finding that 1 inhibits DNA synthesis in the nanomolar range, arrests the cell cycle in the G2/M phases and has severe morphological changes on tumour cells [5]. Furthermore, structure activity relations studies (SAR) revealed even more cytotoxic derivatives with GI50 values in the teens [6, 7]. 

Currently we are conducting further mechanistic experiments as well as preliminary pharmacokinetic and toxicological investigations to elucidate the anticancer properties of the thieno[2,3-b]pyridines.

Biography: Dr Reynisson began his academic career at the University of Iceland where he read chemistry (BSc/MSc). His PhD was obtained from the University of Copenhagen in 2000; the research work was carried out at the Risø national laboratory. He spent two years in Germany as a post-doc at the Max-Planck-Institut für Strahlenchemie (radiation chemistry). He worked for five years at the Institute of Cancer Research in London as a molecular modeller/computational chemist developing anticancer drug candidates. Before he left the United Kingdom for New Zealand he was a lecturer in chemistry at the Nottingham Trent University. He has visited three institutes for half a year each. These are Worcester Polytechnic Institute (MA, USA), Georgia Institute of Technology (GA, USA) and The University of Leipzig (Germany). He is now a Senior Lecturer in computational chemistry and molecular modelling at the School of Chemical Sciences, University of Auckland, New Zealand.
Dr Reynisson’s research interests lie within the field of chemical biology. His main interests are: design of anticancer agents applying in silico methods, DNA damage by ionising radiation and the properties of known drug space as a theoretical framework for medicinal chemistry. His work is based on building models representing the biological system under investigation. The first step is to validate the theoretical methods by comparing them to experimental data. When this criterion is satisfied the model is used to drive the project forward.

References:

[1] V. Kölsch, P.G. Charest, R.A. Firtel, J. Cell Sci., 121 (2008) 551-559. 

[2] J. Reynisson, W. Court, C. O’Neill, J. Day, L. Patterson, E. McDonald, P. Workman, M. Katan, S.A. Eccles, Bioorg. Med. Chem., 17 (2009) 3169-3176. 
[3] R.H. Shoemaker, Nat. Rev. Drug Dis., 6 (2006) 813-823.
[4] L. Feng, I. Reynisdóttir, J. Reynisson, Eur. J. Med. Chem., 54 (2012) 463-469. 
[5] E. Leung, J.M. Hung, D. Barker, J. Reynisson, Med. Chem. Comm., 5 (2014) 99-106. 
[6] H.J. Arabshahi, E. Leung, D. Barker, J. Reynisson, Med. Chem. Comm., 5 (2014) 186-191.
[7] J.M. Hung, H.J. Arabshahi, E. Leung, J. Reynisson, D. Barker, Eur. J. Med. Chem., 86 (2014) 420-437.