KR-39038, a Novel GRK5 Inhibitor, Attenuates Cardiac Hypertrophy and Improves Cardiac Function in Heart Failure
KR-39038, a Novel GRK5 Inhibitor, Attenuates Cardiac Hypertrophy and Improves Cardiac Function in Heart Failure
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DOI：
10.4062/biomolther.2020.129
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发表时间：
2020-09-01
影响因子：
3.7
通讯作者：
Lee, Byung Ho
中科院分区：
文献类型：
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作者：
Lee, Jeong Hyun;Seo, Ho Won;Lee, Byung Ho
G蛋白偶联受体激酶5（GRK 5）是病理性心肌肥厚的重要调节因子，被认为是治疗心力衰竭的潜在靶点。为了发现选择性抑制GRK 5的新型支架，我们鉴定了GRK 5的新型小分子抑制剂KR-39038 [7-（（3-（（4-（（3-氨基丙基）氨基）丁基）氨基）丙基）氨基）-2-（2-氯苯基）-6-氟喹唑啉-4（3 H）-酮]。KR-39038对GRK 5表现出有效的抑制活性（IC 50值=0.02 μ M），并显著抑制新生心肌细胞中血管紧张素II诱导的细胞肥大和HDAC 5磷酸化。在压力超负荷诱导的心脏肥大小鼠模型中，KR-39038（30 mg/kg）每日经口给药14天，显示左心室重量降低43%。此外，KR-39038治疗（10和30 mg/kg/天，p.o.）在冠状动脉结扎后慢性心力衰竭大鼠模型中显示出显著的心脏功能保护和心肌重塑衰减。这些结果表明，有效的GRK 5抑制剂可以有效地减轻实验性心力衰竭中的心脏肥大和功能障碍，并且KR-39038可以作为有效的GRK 5抑制剂用于药学应用。
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 mu M) 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.