ml200176m_si_001.pdf (7.07 MB)
Systematic Chemical Mutagenesis Identifies a Potent Novel Apratoxin A/E Hybrid with Improved in Vivo Antitumor Activity
journal contributionposted on 2015-12-16, 20:20 authored by Qi-Yin Chen, Yanxia Liu, Hendrik Luesch
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.
alanine scanningapratoxins downregulate receptorsreceptor tyrosine kinasessubstrate selectivitygrowth factor ligandssecretory moleculesvivo efficacychiral centerscancer cellsgrowth factorcotranslational translocationVivo Antitumor ActivityApratoxinscytotoxic marinesecretory pathwayDifferential effectsSystematic Chemical Mutagenesis Identifiescolorectal tumor xenograft modelacid substitutionsPotent Novel Apratoxinchemistry effortsnovel mechanismautocrine loopstarget engagement