Chemical Inhibitors of Soluble Adenylyl Cyclase (sAC)

Adenylyl cyclase is the effector enzyme of one of the most widely used signal transduction pathways in mammalian cells. Its product, cyclic adenosine monophosphate (cAMP), acts widely throughout the cytoplasm as a second messenger. A transmembrane adenylyl cyclase (tmAC) is well documented in the literature. In the early 1970s, Dr. Theodore Braun observed soluble adenylyl cyclase activity in cytosolic testis extracts from rats, but was unable to purify the enzyme. Nor was anyone else.

Drs. Lonny Levin and Jochen Buck, investigators at the Weill Cornell Medical College, purified and cloned an isoform of the soluble adenylyl cyclase (sAC) in the late 1990s. Cornell holds the issued patent on the genes and isolated proteins.

The sAC gene is alternatively spliced with isoforms expressed at basal levels in almost all tissues, at higher levels in several epithelia, and at high levels in the testis. Drs. Levin & Buck identified calcium and bicarbonate as key activators of the testicular isoform of sAC, meaning that sAC functions as a bicarbonate sensor and as a pH sensor.

Drs. Levin and Buck have screened a library of compounds against sAC and have identified several hits which they are in process of refining the first small molecule inhibitors of sAC (see Zippin 2004 for examples of a subset of these compounds at work). Screening is ongoing to identify up-regulators of sAC.

The investigators have demonstrated that isoforms of sAC have relevance in the following systems, along with several others that are unpublished:

- maturation & motility of sperm (Pastor-Soler 2003; Sinclair, 2000) - fluid secretion by corneal endothelial cells (Sun 2003)- activation of CREB in the nucleus (Zippin 2004)- insertion of proton pumps in parietal cells (2003 Geibel poster presentation)- neutrophil burst (Han H et al 2005)- Insulin secretion (Published PCT application WO2005US01807)- Neurotrophic mediator (Stessin 2006)Related technologies: CRF D-2282, D-3373, D-3652