Approaches to Targeting Adenylyl Cyclase 1 for Novel Pain Therapeutics

Abstract

Adenylyl cyclases (AC) catalyze the formation of cyclic AMP (cAMP) from ATP and are involved in a number of disease states, making them attractive potential drug targets. Recent preclinical studies have identified neuronal adenylyl cyclase type 1 (AC1) as a novel target for treating chronic pain. AC1 is highly expressed in neuronal tissues associated with pain processing and neuronal plasticity, and studies using AC1 knockout mice provide direct evidence linking AC1 to chronic inflammatory pain conditions. Furthermore, AC1 inhibitors would lack the side effects associated with other agents (e.g. opioids) used to treat chronic inflammatory pain. We have designed our studies to target NOT the conserved P‐site or forskolin‐binding site, but rather a novel approach, targeting the unique protein‐protein interaction of AC1 and calmodulin (CaM). AC1 and AC8 are both activated by CaM; however, the CaM binding domains are unique in structure and location providing an unprecedented opportunity to achieve AC1 selectivity. We hypothesize that developing a small molecule inhibitor of AC1 will allow us to mimic the AC1 knockout phenotype and provide a new avenue for the treatment of chronic inflammatory pain. Through the development and implementation of a novel biochemical high‐throughput screening paradigm we will interrogate a library of 100,000 compounds to identify inhibitors of the AC1/CaM protein‐protein interaction. Hit compounds will be validated and chemically optimized to lead molecules using cellular assays focused on selectivity and potency to guide medicinal chemistry efforts. To date, we have screened 14,080 compounds and identified 18 compounds capable of disrupting the AC1/CaM protein‐protein interaction, a hit rate of 0.13%. We anticipate the identification of selective AC1 inhibitors that will ultimately be improved and applied in models of chronic inflammatory pain.Support or Funding InformationThis work was supported by The National Institutes of Health (1R61NS111070 DLR & VJW), The University of Iowa Center for Biocatalysis and Bioprocessing and the NIH‐sponsored Predoctoral Training Program in Biotechnology (5T32GM008365 JBO).