The development of 2-benzimidazole substituted pyrimidine based inhibitors of lymphocyte specific kinase (Lck).
This communication details the synthesis, biological activity, and binding mode of a novel class of 2-benzimidazole substituted pyrimidines. The most potent analogs disclosed showed low nanomolar activity for the inhibition of Lck kinase and a representative analog was co-crystallized with Hck (a structurally related member of the Src family kinases).
Sabat
Mark
M
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd., Mason, OH 45040, USA. Mark.Sabat@Takedasd.com <Mark.Sabat@Takedasd.com>
VanRens
John C
JC
Laufersweiler
Matthew J
MJ
Brugel
Todd A
TA
Maier
Jennifer
J
Golebiowski
Adam
A
De
Biswanath
B
Easwaran
Vijayasurian
V
Hsieh
Lily C
LC
Walter
Richard L
RL
Mekel
Marlene J
MJ
Evdokimov
Artem
A
Janusz
Michael J
MJ
D001562:Benzimidazoles / Q000737:chemistry*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051572:Proto-Oncogene Proteins c-hck / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C031000:benzimidazole; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051572:Proto-Oncogene Proteins c-hck; C030986:pyrimidine