Samu Melkko; Luca Mannocci; Christoph E. Dumelin; Alessandra Villa; Roberto Sommavilla; Yixin Zhang; Markus G. Grütter; Nadine Keller; Lutz Jermutus; Ronald H. Jackson; Jörg Scheuermann; Dario Neri
ChemMedChem, 2010, 5, 4, 584-590
https://doi.org/10.1002/cmdc.200900520

Abstract

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 (Kd) of 930 nm and was able to compete with a Bak-derived BH3 peptide, an antagonist of Bcl-xL function.