Design, synthesis and selection of DNA-encoded small-molecule libraries.
Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.
Clark
Matthew A
MA
Praecis Pharmaceuticals, Waltham, Massachusetts, USA
Acharya
Raksha A
RA
Arico-Muendel
Christopher C
CC
Belyanskaya
Svetlana L
SL
Benjamin
Dennis R
DR
Carlson
Neil R
NR
Centrella
Paolo A
PA
Chiu
Cynthia H
CH
Creaser
Steffen P
SP
Cuozzo
John W
JW
Davie
Christopher P
CP
Ding
Yun
Y
Franklin
G Joseph
GJ
Franzen
Kurt D
KD
Gefter
Malcolm L
ML
Hale
Steven P
SP
Hansen
Nils J V
NJ
Israel
David I
DI
Jiang
Jinwei
J
Kavarana
Malcolm J
MJ
Kelley
Michael S
MS
Kollmann
Christopher S
CS
Li
Fan
F
Lind
Kenneth
K
Mataruse
Sibongile
S
Medeiros
Patricia F
PF
Messer
Jeffrey A
JA
Myers
Paul
P
O'Keefe
Heather
H
Oliff
Matthew C
MC
Rise
Cecil E
CE
Satz
Alexander L
AL
Skinner
Steven R
SR
Svendsen
Jennifer L
JL
Tang
Lujia
L
van Vloten
Kurt
K
Wagner
Richard W
RW
Yao
Gang
G
Zhao
Baoguang
B
Morgan
Barry A
BA
D000818:Animals; D064127:Aurora Kinases; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D015195:Drug Design; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D004247:DNA; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases