Molecular Approaches to Discover Marine Natural Product Anticancer Leads - An Update from a Drug Discovery Group Collaboration

摘要

This paper outlines the results of a collaborative program begun in 1990 under the NIH National Cooperative Drug Discovery Group (NCDDG) program. It involves the unified research of a multi-institutional group from both academic and corporate laboratories. Our working hypothesis is that targets identified through basic molecular and cell biology studies are relevant for the treatment of human cancers. Thus, a broad range of primary biochemical assays have guided the examination of extracts obtained from marine organisms (both collected and cultured) and purified marine natural products. The goal is to discover small molecules effective against these biological targets. An ever-changing panel of assays focus on a number of cancer relevant targets associated with the cell cycle, signal transduction, angiogenesis or apoptosis. A massive library of materials has been assembled for evaluation in the screens and it consists of more than 900 compounds and 16,000 extracts. We believe that these samples have enormous potential for chemodiveristy and progress to date supports this contention. The first part of the paper focuses on highlights from the period 1995-1999. The two most important developments were that the bengamide and the psammaplin families provided important insights leading to the development of two compounds, LAF-389 and NVP-LAQ824. These were both advanced to Phase I anti-cancer clinical trials. A sampling of recent discoveries, including current leads in development is also discussed. Attention then turns to new technologies and strategies aimed at shortening the time interval from an initial lead candidate discovery to assessment of its future therapeutic potential.