Discovery of pyrimidine benzimidazoles as Src-family selective Lck inhibitors. Part II.
A series of 4-amino-6-benzimidazole-pyrimidines was designed to target lymphocyte-specific tyrosine kinase (Lck), a member of the Src-family kinases (SFKs). These type II inhibitors were optimized using a cellular Lck-dependent proliferation assay and are capable of inhibiting Lck at single-digit nanomolar concentrations. This scaffold is likely to serve a valuable template for developing potent inhibitors of a number of SFKs.
Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA. gzhang@gnf.org
Guobao
G
Zhang
Pingda
P
Ren
Nathanael S
NS
Gray
Taebo
T
Sim
Xia
X
Wang
Yi
Y
Liu
Jianwei
J
Che
Weitong
W
Dong
Shin-Shay
SS
Tian
Mark L
ML
Sandberg
Tracy A
TA
Spalding
Russell
R
Romeo
Maya
M
Iskandar
Zhiliang
Z
Wang
H Martin
HM
Seidel
Donald S
DS
Karanewsky
Yun
Y
He
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D055808:Drug Discovery; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C030986:pyrimidine