Discovery, SAR, and X-ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library.
As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (R)-3-((1-(5-bromothiophene-2-carbonyl)pyrrolidin-3-yl)oxy)-N-methyl-2'-(methylsulfonamido)-[1,1'-biphenyl]-4-carboxamide (15e) from a novel compound library synthesized via on-DNA Suzuki-Miyaura cross-coupling showed BCATm inhibitory activity with IC50 = 2.0 μM. A protein crystal structure of 15e revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors.
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Hongfeng
H
Deng
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jingye
J
Zhou
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Flora S
FS
Sundersingh
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jennifer
J
Summerfield
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Don
D
Somers
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jeffrey A
JA
Messer
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Alexander L
AL
Satz
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Nicolas
N
Ancellin
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher C
CC
Arico-Muendel
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Katie L
KL
Sargent Bedard
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Arthur
A
Beljean
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Svetlana L
SL
Belyanskaya
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Ryan
R
Bingham
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Sarah E
SE
Smith
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Eric
E
Boursier
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Paul
P
Carter
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Paolo A
PA
Centrella
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Matthew A
MA
Clark
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Chun-Wa
CW
Chung
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher P
CP
Davie
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Jennifer L
JL
Delorey
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Yun
Y
Ding
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
G Joseph
GJ
Franklin
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
LaShadric C
LC
Grady
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
Kenny
K
Herry
Medicines Research Centre, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Herts SG1 2NY, U.K.
Clare
C
Hobbs
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Christopher S
CS
Kollmann
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Barry A
BA
Morgan
Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
Laura J
LJ
Pothier Kaushansky
Chemistry Department, Brandeis University , Waltham, Massachusetts 02453, United States.
Quan
Q
Zhou
BCATm; DNA Encoded Library; ELT; obesity; on-DNA Suzuki−Miyaura cross-coupling reaction