Abstract
PL02-02
One of the most vexing problems in life science is that of “undruggability,” the difficulty of targeting certain biological macromolecules in vivo using existing drug or ligand discovery technologies. It has been estimated that as many as 80-90% of all potential targets, including many that have been extensively validated in humans and in animal models, are undruggable. The Verdine laboratory is developing powerful new chemistry-based platform technologies to address these undruggable targets. Specifically, the lab is developing “synthetic biologics,” molecules that, like biologics, possess the ability to target large flat surfaces, but that, like small molecules, are fully synthetic and hence can be modified at will. Progress on the development of synthetic biologics will be reviewed in this talk. Walensky, L. D.; Kung, A. L.; Escher, I.; Malia, T. J.; Barbuto, S.; Wright, R.; Wagner, G.; Verdine, G. L.; Korsmeyer, S. J. “Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix,” Science 2004, 305, 1466-1470. Walensky, L. D.; Pitter, K.; Morash, J.; Oh, K. J.; Barbuto, S.; Fisher, J.; Smith, E.; Verdine, G. L.; Korsmeyer, S. J. “A Stapled BID BH3 Helix Directly Binds and Activates BAX,” Mol. Cell 2006, 24, 199-210. Bernal, F.; Tyler, A. F.; Korsmeyer, S. J.; Walensky, L. D.; Verdine, G. L. “Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide,” J. Am. Chem. Soc. 2007, 2456-2457.
First AACR Centennial Conference on Translational Cancer Medicine-- Nov 4-8, 2007; Singapore