Natural product drug discovery: the successful optimization of ISP-1 and halichondrin B

The concept that natural products provide excellent leads for drug discovery, ultimately producing viable drugs, is a widely accepted view. Natural products embody inherent structural complexity and biological activity which often leads to new targets, pathways, or modes of action. The challenge lies in identifying quality natural product scaffolds that can ultimately result in a drug. Two recently approved drugs originating from unlikely natural product leads, ISP-1 and halichondrin B, were examples of such high quality scaffolds. In initial testing, both compounds displayed excellent in vitro potency, but more importantly were amenable to chemical optimization. This combination of unique biological activity plus the generation of structural activity relationships (SAR) may be early indicators of a high quality natural product scaffold worthy of additional studies.