Toward the development of a potent and selective organoruthenium mammalian sterile 20 kinase inhibitor.
Mammalian sterile 20 (MST1) kinase, a member of the sterile 20 (Ste-20) family of proteins, is a proapoptotic cytosolic kinase that plays an important role in the cellular response to oxidative stress. In this study, we report on the development of a potent and selective MST1 kinase inhibitor based on a ruthenium half-sandwich scaffold. We show that the enantiopure organoruthenium inhibitor, 9E1, has an IC50 value of 45 nM for MST1 and a greater than 25-fold inhibitor selectivity over the related Ste-20 kinases, p21 activated kinase 1 (PAK1), and p21 activated kinase 4 (PAK4) and an almost 10-fold selectivity over the related thousand-and-one amino acids kinase 2 (TAO2). Compound 9E1 also displays a promising selectivity profile against unrelated protein kinases; however, the proto-oncogene serine/threonine protein kinase PIM1 (PIM-1) and glycogen synthase kinase 3 (GSK-3beta) are inhibited with IC50 values in the low nanomolar range. We also show that 9E1 can inhibit MST1 function in cells. A cocrystal structure of a related compound with PIM-1 and a homology model with MST1 reveals the binding mode of this scaffold to MST1 and provides a starting point for the development of improved MST1 kinase inhibitors for possible therapeutic application.
Anand
Ruchi
R
Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Maksimoska
Jasna
J
Pagano
Nicholas
N
Wong
Eric Y
EY
Gimotty
Phyllis A
PA
Diamond
Scott L
SL
Meggers
Eric
E
Marmorstein
Ronen
R
D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000090063:Proto-Oncogene Mas; D017975:Ruthenium Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000099317:Hippo Kinases
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D017975:Ruthenium Compounds; C000715470:MAS1 protein, human; C095566:STK4 protein, human; D000099317:Hippo Kinases