title: Hydroxamate based inhibitors of adenylyl cyclase. Part 1: the effect of acyclic linkers on P-site binding.
abstract: The adenylyl cyclases (ACs) are a family of enzymes that are key elements of signal transduction by virtue of their ability to convert ATP to cAMP. The catalytic mechanism of this transformation proceeds through initial binding of ATP to the purine binding site (P-site) followed by metal mediated cyclization with loss of pyrophosphate. Crystallographic analysis of ACs with known inhibitors reveals the presence of two metals in the active site. Presently, nine isoforms of adenylyl cyclase are known and unique isoform combinations are expressed in a tissue specific manner. The development of isoform specific inhibitors of adenylyl cyclase may prove to be a useful strategy toward the design of novel therapeutic agents. In order to develop novel AC inhibitors, we have chosen a design approach utilizing molecules with the adenine ring system joined to a metal-coordinating hydroxamic acid via flexible acyclic linkers. The designed inhibitors were assayed against type V AC with the size and heteroatom content of the linkers varied to probe the interaction of the nucleotide and metal binding sites within the enzyme.
authors.affiliation: Millennium Pharmaceuticals, Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. san.levy@mpi.com
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Charles
authors.initials: C
authors.lastname: Marlowe
authors.forename: Kim
authors.initials: K
authors.lastname: Kane-Maguire
authors.forename: Ming
authors.initials: M
authors.lastname: Bao
authors.forename: Diana
authors.initials: D
authors.lastname: Cherbavaz
authors.forename: James
authors.initials: J
authors.lastname: Tomlinson
authors.forename: David
authors.initials: D
authors.lastname: Sedlock
authors.forename: Robert
authors.initials: R
authors.lastname: Scarborough
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008274:Magnesium / Q000737:chemistry; D011487:Protein Conformation; D011983:Receptors, Purinergic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D007527:Isoenzymes; D011983:Receptors, Purinergic; D008274:Magnesium