title: Designed TPR modules as novel anticancer agents.
abstract: Molecules specifically designed to modulate protein-protein interactions have tremendous potential as novel therapeutic agents. One important anticancer target is the chaperone Hsp90, whose activity is essential for the folding of many oncogenic proteins, including HER2, IGFIR, AKT, RAF-1, and FLT-3. Here we report the design and characterization of new tetratricopeptide repeat modules, which bind to the C-terminus of Hsp90 with higher affinity and with greater specificity than natural Hsp90-binding co-chaperones. Thus, when these modules are introduced into the cell, they out-compete endogenous co-chaperones for binding, thereby inhibiting Hsp90 function. The effect of Hsp90 inhibition in this fashion is dramatic; HER2 levels are substantially decreased and BT474 HER2 positive breast cancer cells are killed. Our designs thus provide new tools with which to dissect the mechanism of Hsp90-mediated protein folding and also open the door to the development of an entirely new class of anticancer agents.
authors: Department of Molecular Biophysics & Biochemistry, Yale University, 266 Whitney Avenue, New Haven, Connecticut 06520, USA. lynne.regan@yale.edu
authors: Aitziber L
authors: AL
authors: Cortajarena
authors: Fang
authors: F
authors: Yi
authors: Lynne
authors: L
authors: Regan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D015536:Down-Regulation; D015195:Drug Design; D006360:Heat-Shock Proteins / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012680:Sensitivity and Specificity; D020349:Surface Plasmon Resonance
chemical_list: D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; D008024:Ligands; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases