Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library.
Bcl-xL is an antiapoptotic member of the Bcl-2 protein family and an attractive target for the development of anticancer agents. Here we describe the isolation of binders to Bcl-xL from a DNA-encoded chemical library using affinity-capture selections and massively parallel high-throughput sequencing of >30,000 sequence tags of library members. The most potent binder identified, compound 19/93 [(R)-3-(amido indomethacin)-4-(naphthalen-1-yl)butanoic acid], bound to Bcl-xL with a dissociation constant (K(d)) of 930 nM and was able to compete with a Bak-derived BH3 peptide, an antagonist of Bcl-xL function.
Melkko
Samu
S
Philochem AG, Wolfgang-Pauli-Str 10, 8093 Zürich, Switzerland.
Mannocci
Luca
L
Dumelin
Christoph E
CE
Villa
Alessandra
A
Sommavilla
Roberto
R
Zhang
Yixin
Y
Grütter
Markus G
MG
Keller
Nadine
N
Jermutus
Lutz
L
Jackson
Ronald H
RH
Scheuermann
Jörg
J
Neri
Dario
D
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D006801:Humans; D017422:Sequence Analysis, DNA; D054852:Small Molecule Libraries; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D054852:Small Molecule Libraries; D051020:bcl-X Protein; D004247:DNA