Biased Agonism In GPCR Drug Discovery: Application To Somatostatin Agonists

Project Summary Neuropeptide somatostatin analogs are important therapeutics for the treatment of hormone secreting tumors with annual sales of$BHowevercurrently available peptide depots are effective in only half the patients with growth hormone secreting tumorsand patients with carcinoid tumors can rapidly become resistant to these drugsSomatostatin analogs act by stimulating the GPCR sst Abut the currently available agents cause desensitization via internalization of the same receptorresulting in reduced or complete loss of efficacyWe hypothesized that biased agonists of sst A that maintain strong Gi activationbut do not cause desensitizationwould normalize hormone levels in a greater percentage of patients and improve efficacy in patients not adequately controlled by currently available agentsIn Phase Iwe began developing compounds to test this hypothesis using assays for both receptor activation and internalization to identify several small moleculenon peptide agonists that are indeed potent activators of Gibut with far less propensity for inducing receptor internalization and desensitizationThese early results paved the way for Phase IIin which we optimized the leads identified in Phase I to identify compounds with sub nanomolar potencyselectivity versus a number of off target activitiesand drug like properties ultimately leading to a Development CandidateThis compound is effective in both acute and chronic studies of GH and IGF I suppression in ratsexhibits good drug like characteristics including oral bioavailability and half life consistent with anticipated once a day dosing in humanand a good safety margin based on preliminary rat studiesThe goal of this Phase IIB project is to optimize process chemistry and prepare material which will then be used to conduct IND enabling toxicology studiesThis will enable a Phase I clinical trial of the first orally bioavailablebiased somatostatin agonist for the treatment of hormone secreting tumorsOur innovative approach towards the identification of such an agent has proactively incorporated a set of receptor regulatory assaysand if successfulpromises to deliver a new cost effective therapeutic agent with a novel pharmacological profile that leads to both improved efficacy and durability of effectImportantlythe GPCR family is a rich source of proven targets for drug discoverywhich share common regulatory and signaling mechanismsThereforeif successfulthis work will not only provide improved agents for patients with hormone secreting tumorsbut will also support a general novel strategy for optimizing agonist drugs that can be exploited to target many other GPCRs