Synthesis and biological evaluation of a 5-6-5 imidazole-phenyl-thiazole based alpha-helix mimetic.
The development of small molecules that disrupt protein-protein interactions is a key goal in addressing a number of disease states. The alpha-helix is commonly found at protein interaction interfaces and has been the focus of substantial small molecule mimetic efforts. One of the primary drawbacks of many small molecule alpha-helix mimetics is their hydrophobic core structures. To address this problem we have developed a novel scaffold based on a more water soluble 5-6-5 imidazole-phenyl-thiazole core. An inhibitor of this class has been shown to disrupt the Cdc42/Dbs protein-protein interaction at micromolar concentrations and may be useful in overcoming Cdc42-induced tumor resistance to anticancer therapies.
Cummings
Christopher G
CG
Department of Chemistry, Yale University, P.O. Box 20810, New Haven, Connecticut 06520, USA.
Ross
Nathan T
NT
Katt
William P
WP
Hamilton
Andrew D
AD
D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis
D007093:Imidazoles; D013844:Thiazoles; D020764:cdc42 GTP-Binding Protein