Apratoxins are cytotoxic marine natural products that prevent cotranslational translocation early in the secretory pathway. We showed that apratoxins downregulate receptors and
growth factor ligands, giving a one-two punch to
cancer cells, particularly those that rely on autocrine loops. Through total synthesis, we tested the effects of amino acid substitutions, including
alanine scanning, on the downregulation of
receptor tyrosine kinases and
vascular endothelial growth factor A (
VEGF-A) and probed the stereospecificity of target engagement by epimerization of selected chiral centers. Differential effects on two types of secretory molecules suggest that the apratoxins' substrate selectivity with respect to inhibition of secretion may be tuned through structural modifications to provide tailored
therapy. Our structure-activity relationship studies and medicinal chemistry efforts led to a potent inhibitor with in vivo efficacy in a
colorectal tumor xenograft model without irreversible toxicity exerted by
apratoxin A, demonstrating that this novel mechanism of action has therapeutic potential.