Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)584-590
Number of pages7
JournalChemMedChem
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 6 2010

Fingerprint

Small Molecule Libraries
Butyric Acid
Indomethacin
Antineoplastic Agents
Libraries
Binders
Molecules
DNA
Proteins
Throughput
Bax protein (53-86)

Keywords

  • Affinity-based screening
  • Apoptosis
  • Bcl-xL
  • High-throughput
  • Indomethacin
  • Libraries
  • Sequencing

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Melkko, S., Mannocci, L., Dumelin, C. E., Villa, A., Sommavilla, R., Zhang, Y., ... Neri, D. (2010). Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library. ChemMedChem, 5(4), 584-590. https://doi.org/10.1002/cmdc.200900520

Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library. / Melkko, Samu; Mannocci, Luca; Dumelin, Christoph E.; Villa, Alessandra; Sommavilla, Roberto; Zhang, Yixin; Grütter, Markus G.; Keller, Nadine; Jermutus, Lutz; Jackson, Ronald H.; Scheuermann, Jörg; Neri, Dario.

In: ChemMedChem, Vol. 5, No. 4, 06.04.2010, p. 584-590.

Research output: Contribution to journalArticle

Melkko, S, Mannocci, L, Dumelin, CE, Villa, A, Sommavilla, R, Zhang, Y, Grütter, MG, Keller, N, Jermutus, L, Jackson, RH, Scheuermann, J & Neri, D 2010, 'Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library', ChemMedChem, vol. 5, no. 4, pp. 584-590. https://doi.org/10.1002/cmdc.200900520
Melkko, Samu ; Mannocci, Luca ; Dumelin, Christoph E. ; Villa, Alessandra ; Sommavilla, Roberto ; Zhang, Yixin ; Grütter, Markus G. ; Keller, Nadine ; Jermutus, Lutz ; Jackson, Ronald H. ; Scheuermann, Jörg ; Neri, Dario. / Isolation of a small-molecule inhibitor of the antiapoptotic protein Bcl-xL from a DNA-encoded chemical library. In: ChemMedChem. 2010 ; Vol. 5, No. 4. pp. 584-590.
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