Mechanism-based screening for cancer therapeutics with examples from the discovery of marine natural product-based HIF-1 inhibitors

Abstract

Recent advances in cancer genetics combined with an increasing number of new methods in molecular and cell biology provide exciting new antitumor drug targets and a wide array of means to design bioassay systems for the discovery of novel cancer chemotherapeutics. Marine natural products continue to play a vital role in molecular-targeted antitumor drug discovery. Although most recognize the critical and expanding role mechanism-based antitumor bioassays play in modern anticancer drug discovery, few natural products chemists have specific training in bioassay technology. Critical bioassay development factors are outlined and introduced at a level intended to provide a basic understanding to a general audience. These include molecular target identification, antitumor target validation, selection of assayable biochemical processes, data acquisition methods, experimental controls, bioassay validation and statistical methods, experimental artifacts, active compound identification, and the dereplication of nuisance compounds. Marine natural products have been identified that inhibit the activation of the anticancer drug target hypoxia-inducible factor-1 (HIF-1). Bioassay systems and recent results from marine HIF-1 inhibitor discovery programs are used to illustrate important factors that must be considered when using molecular-targeted antitumor bioassay methods.