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

• Published in: Bioorganic & medicinal chemistry Vol. 44; p. 116282
• Main Authors: Daguer, Jean-Pierre, Gonse, Arthur, Shchukin, Yevhenii, Farrera-Soler, Lluc, Barluenga, Sofia, Winssinger, Nicolas
• Format: Journal Article
• Language: English
• Published: England 15.08.2021
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; bcl-X Protein - antagonists & inhibitors; Cell Proliferation - drug effects; Cell Survival - drug effects; DNA - chemistry; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; K562 Cells; Molecular Structure; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Bcl-2; DNA-encoded library; Fragment based drug discovery; Peptide Nucleic Acid (PNA); Bcl-X(L)
• DOI: 10.1016/j.bmc.2021.116282

A dual Bcl-X / 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.