Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.
A strategy for targeting protein kinases with large ATP-binding sites by using bulky and rigid octahedral ruthenium complexes as structural scaffolds is presented. A highly potent and selective GSK3 and Pim1 half-sandwich complex NP309 was successfully converted into a PAK1 inhibitor by making use of the large octahedral compounds Lambda-FL172 and Lambda-FL411 in which the cyclopentadienyl moiety of NP309 is replaced by a chloride and sterically demanding diimine ligands. A 1.65 A cocrystal structure of PAK1 with Lambda-FL172 reveals how the large coordination sphere of the ruthenium complex matches the size of the active site and serves as a yardstick to discriminate between otherwise closely related binding sites.
Maksimoska
Jasna
J
The Wistar Institute and University of Pennsylvania, Department of Chemistry, Philadelphia, Pennsylvania 19104, USA.
Feng
Li
L
Harms
Klaus
K
Yi
Chunling
C
Kissil
Joseph
J
Marmorstein
Ronen
R
Meggers
Eric
E
D000818:Animals; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017975:Ruthenium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity
D047428:Protein Kinase Inhibitors; D017975:Ruthenium Compounds; D011494:Protein Kinases