KR-39038, a Novel GRK5 Inhibitor, Attenuates Cardiac Hypertrophy and Improves Cardiac Function in Heart Failure

  • Lee, Jeong Hyun (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Seo, Ho Won (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Ryu, Jae Yong (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Lim, Chae Jo (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Yi, Kyu Yang (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Oh, Kwang-Seok (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology) ;
  • Lee, Byung Ho (Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology)
  • Received : 2020.07.17
  • Accepted : 2020.08.05
  • Published : 2020.09.01


G protein-coupled receptor kinase 5 (GRK5) has been considered as a potential target for the treatment of heart failure as it has been reported to be an important regulator of pathological cardiac hypertrophy. To discover novel scaffolds that selectively inhibit GRK5, we have identified a novel small molecule inhibitor of GRK5, KR-39038 [7-((3-((4-((3-aminopropyl)amino)butyl)amino)propyl)amino)-2-(2-chlorophenyl)-6-fluoroquinazolin-4(3H)-one]. KR-39038 exhibited potent inhibitory activity (IC50 value=0.02 µM) against GRK5 and significantly inhibited angiotensin II-induced cellular hypertrophy and HDAC5 phosphorylation in neonatal cardiomyocytes. In the pressure overload-induced cardiac hypertrophy mouse model, the daily oral administration of KR-39038 (30 mg/kg) for 14 days showed a 43% reduction in the left ventricular weight. Besides, KR-39038 treatment (10 and 30 mg/kg/day, p.o.) showed significant preservation of cardiac function and attenuation of myocardial remodeling in a rat model of chronic heart failure following coronary artery ligation. These results suggest that potent GRK5 inhibitor could effectively attenuate both cardiac hypertrophy and dysfunction in experimental heart failure, and KR-39038 may be useful as an effective GRK5 inhibitor for pharmaceutical applications.



This research was supported by Korea Drug Development Fund (KDDF) funded by MSIP, MOTIE and MOHW (KDDF-201603-01, Republic of Korea).


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