Synthetic analogs of the marine natural product hemiasterlin: Optimization and discovery of E7974, a novel and potent antitumor agent

1212 Hemiasterlin is a tripeptide natural product isolated from several marine sponges (e.g., Hemiasterella minor ). Hemiasterlin has been shown to have potent anticancer activity in vitro in cultured cancer cells, and in vivo in animal models of cancer. Hemiasterlin acts via a tubulin-based antimitotic mechanism inhibiting microtubule polymerization. Unfortunately, hemiasterlin has a small therapeutic window in vivo in mouse tumor xenograft models. Here we describe the synthesis of a variety of analogs of hemiasterlin, and their in vitro and in vivo anticancer activities. In particular, optimization of the N-terminal amino acid of hemiasterlin derivatives resulted in compounds with high potency against human cancer cells in vitro and low susceptibility to P-glycoprotein-mediated drug efflux. These synthetic efforts resulted in the discovery of E7974, a potent inhibitor of cancer cell growth which retains strong activity in multidrug-resistant cancer cells and xenograft tumor models.