Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT).
The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Yun
Y
Ding
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Heather
H
O'Keefe
Tedor Pharma, Inc. , 400 Highland Corporate Drive, Cumberland, Rhode Island 02864, United States.
Jennifer L
JL
DeLorey
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
David I
DI
Israel
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jeffrey A
JA
Messer
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Cynthia H
CH
Chiu
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Steven R
SR
Skinner
Biological Reagent and Assay Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
Rosalie E
RE
Matico
Biological Reagent and Assay Development, GlaxoSmithKline , 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
Monique F
MF
Murray-Thompson
Tufts Healthcare Institute , 136 Harrison Avenue, Boston, Massachusetts 02111, United States.
Fan
F
Li
X-Chem, Inc. , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
Matthew A
MA
Clark
X-Chem, Inc. , 100 Beaver Street, Waltham, Massachusetts 02453, United States.
John W
JW
Cuozzo
Platform Technology & Science, GlaxoSmithKline , ELT-Boston, 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher
C
Arico-Muendel
Center for Drug Discovery, Baylor College of Medicine , One Baylor Plaza, Houston, Texas 77030, United States.
Barry A
BA
Morgan
ADAMTS-4; DNA-encoded library; inhibitors