The discovery of adenylyl cyclase isoform-selective small molecules has proven difficult but would facilitate the validation of specific isoforms as therapeutic targets. For example, adenylyl cyclase 2 (AC2) is an isoform that is potentially involved in skeletal muscle physiology, lung diseases, neuroendocrine tumors, and colorectal cancer. Identification of chemical probes for AC2 is particularly important because there are no published genetic deletion studies and few small molecule modulators. The present report describes the development and implementation of an intact-cell small molecule screening approach and subsequent validation paradigms for the discovery of AC2 inhibitors. The screening effort identified SKF-83566 [8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide] as a selective AC2 inhibitor, superior for selectivity of AC2 compared with currently available adenylyl cyclase inhibitors.
See article at J Pharmacol Exp Ther 2013, 347:276–287.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics