G protein-coupled receptor kinases (GRKs) regulate cell signaling by initiating the desensitization of active G protein-coupled receptors. CCG-215022 is a potently GRKs inhibitor with IC50 values of 3.9nM, 0.15nM, 0.38nM and 120nM for GRK1, GRK2, GRK5 and PKA, respectively[1]. Treatment of murine cardiomyocytes with 0.5μM CCG215022 resulted in significantly increased contractility at 20-fold lower concentrations than paroxetine, an inhibitor with more modest selectivity for GRK2[1]. CCG-215022 also inhibited the desensitization of H1 or P2Y2 receptor driven PLC/Ca2+ activity in ULTR and MSMC with IC50 values of 5.51μM and 5.53μM, respectively[2]. In vivo, intraperitoneal administration CCG-215022 at 20mg/kg every 3 days for 21 days significantly reduce tumor growth in ERMS and ARMS xenograft tumor models[3].
作用机制
The amide-linked pyridine extension of CCG215022 forms additional hydrogen bonds via its amide with the P-loop and via the pyridine nitrogen with Lys220 and Asp329 [4].
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