MRIA9

MRIA9 is described as a selective SIK-inhibitor with an in vitro potency of 55/48/22 nM for SIK1/2/3 (33Pan Qinase activity assay data). Against 443 screened kinases at 1 µM concentration of MRIA9, the following off-targets (35% residual activity) were identified and their respective IC50 values were determined in an enzymatic assay: PAK2 (41 nM), PAK3 (140 nM), and PAK1 (580 nM), KHS1 (240 nM), NLK (250 nM), and MAP2K4 (830 nM). A NanoBRET assay showed cellular target engagement of 516/180/127 nM for SIK1/2/3 - providing decent selectivity towards NLK (3100 nM), TIE2 (6000 nM), PKN3 (6700 nM), and KHS1 (13000 nM). PAK1/2/3 were unable to trace in cellulo. However, in combination with the selective allosteric inhibitor NVS-PAK1, MRIA9 can be used as a chemical probe for the SIK kinase family, being more selective and better characterized than other SIK inhibitors HG-9-91-01, YKL-05-099, and ARN-3236. In addition, MR7 serves as a structural similar control compound.