ISPO

Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Molecular targets for cancer therapy in the post-genome era

P Workman

CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey UK, paulw@icr.ac.uk

Cancer drug discovery is being revolutionized by a combination of scientific and technological breakthroughs that should allow rapid development of new agents with the potential for greater activity and reduced toxicity. In this presentation I will describe recent developments in the Center which are designed to take full advantage of these breakthroughs in an academic research institute setting. Particular emphasis is placed on new molecular targets that are responsible for driving the malignant progression of human cancer. We believe that therapeutic intervention at such loci provides the best opportunity for therapeutic efficacy and selectivity. Advances in genomics, particularly the output of the Human Genome and Cancer Genome Projects, provides unprecedented potential for the identification of new targets. The particular challenge in the post-genome era is to identify gene function and to validate and prioritize targets for drug discovery. Our small molecule drug discovery capability is boosted by the establishment of a high throughput screening laboratory and the creation of a 60K compound library. This is complemented by collaborations with structural biology and molecular modeling colleagues. Optimization of small molecule leads is accelerated by the use of robotic combinatorial chemistry alongside medicinal chemistry. Profiling of compounds through mechanism-based test cascades is accelerated by high throughput biological assays. Conversion of in vitro leads to give in vivo drug-like properties is a major hurdle and we are using cassette (or cocktail) dosing to select compounds with the best pharmacokinetic properties. Antitumor activity is demonstrated using the hollow fiber assay and molecularly characterized or engineered human tumour xenografts. Incorporation of mechanistic endpoints into preclinical and early clinical development is essential and we are using both molecular and imaging endpoints. We have found the use of gene expression microarrays to be particularly valuable for the investigation of mechanism of action and the discovery of pharmacodynamic endpoints. The Center's small molecule drug discovery strategy, involving both in-house and collaborative projects, will be illustrated by the development of a range of agents, including inhibitors of the Hsp90 molecular chaperone and on histone acetyl transferase.

KEY WORDS: cancer drug, chemistry, molecular targets, human genome project.

For more information, contact paulw@icr.ac.uk

Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on anticancer strategies.

http://www.cancerprev.org/Journal/Issues/24/101/401/3830