2. Academic Validation
  3. Dual Bcl-XL /Bcl-2 inhibitors discovered from DNA-encoded libraries using a fragment pairing strategy

Dual Bcl-XL /Bcl-2 inhibitors discovered from DNA-encoded libraries using a fragment pairing strategy

  • Bioorg Med Chem. 2021 Aug 15:44:116282. doi: 10.1016/j.bmc.2021.116282.
Jean-Pierre Daguer 1,  Arthur Gonse 1,  Yevhenii Shchukin 1,  Lluc Farrera-Soler 1,  Sofia Barluenga 1,  Nicolas Winssinger 2
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Sciences, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland.
  • 2 Department of Organic Chemistry, Faculty of Sciences, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland. Electronic address: nicolas.winssinger@unige.ch.
PMID: 34216984 DOI: 10.1016/j.bmc.2021.116282
Abstract

A dual Bcl-XL / Bcl-2 Inhibitor was discovered from DNA-encoded libraries using a two steps process. In the first step, DNA was used to pair PNA-encoded fragments exploring > 250 000 combinations. In the second step, a focused library combining the selected fragments with linkers of different lengths and geometries led to the identification of tight binding adducts that were further investigated for their selective target engagement in pull-down assays, for their affinity by SPR, and their selectivity in a cytotoxicity assay. The best compound showed comparable cellular activity to venetoclax, the first-in-class therapeutic targeting Bcl-2.

Keywords

Bcl-2; Bcl-X(L); DNA-encoded library; Fragment based drug discovery; Peptide Nucleic Acid (PNA).

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