Background:

BIX 02565 is a novel inhibitor of ribosomal S6 kinase 2 with IC50 value of 1 nM [1].

Ribosomal S6 kinase (RSK) is a Na/H exchanger (NHE) -activating factor and is important for pH maintenance during the early phase of cellular stress. While, NHE activation leads to Ca2+ overload and cardiac hypertrophy over longer periods [2].

BIX 02565 is a novel RSK2 inhibitor. Also, BIX 02565 inhibited adrenergic ɑ1A-, ɑ1B-, ɑ1D-, ɑ2A-, β2- and imidazoline I2 receptors with IC50 values ranging from 0.052 to 1.820 μM. These receptors played important roles in the regulation of vascular tone and cardiac function [2]. Also, BIX 02565 inhibited LRRK2 and PRKD1 with IC50 values of 16 and 35 nM [1].

In the rat CV screen, BIX 02565 (1, 3 and 10 mg/kg) significantly decreased heart rate (-93 +13 beats/min) and mean arterial pressure (MAP: to -65 +6 mm Hg below baseline). In telemetry-instrumented rats, BIX 02565 (30, 100 and 300 mg/kg for 4 days) reduced MAP (to -39 + 4 mm Hg) in a concentration-dependent way [2].

参考文献:
[1].  Kirrane TM, Boyer SJ, Burke J, et al. Indole RSK inhibitors. Part 2: optimization of cell potency and kinase selectivity. Bioorg Med Chem Lett, 2012, 22(1): 738-742.
[2].  Fryer RM, Muthukumarana A, Chen RR, et al. Mitigation of off-target adrenergic binding and effects on cardiovascular function in the discovery of novel ribosomal S6 kinase 2 inhibitors. J Pharmacol Exp Ther, 2012, 340(3): 492-500.