TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics

Kunig V. B. K., Potowski M., Akbarzadeh M., Klika Škopić M., dos Santos Smith D., Arendt L., ...Daha Fazla

Angewandte Chemie - International Edition, cilt.59, sa.46, ss.20338-20342, 2020 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 59 Sayı: 46
  • Basım Tarihi: 2020
  • Doi Numarası: 10.1002/anie.202006280
  • Dergi Adı: Angewandte Chemie - International Edition
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, L'Année philologique, Agricultural & Environmental Science Database, Applied Science & Technology Source, Aquatic Science & Fisheries Abstracts (ASFA), CAB Abstracts, Chimica, Compendex, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.20338-20342
  • Anahtar Kelimeler: combinatorial chemistry, DNA-encoded library, peptidomimetics, protein-protein interaction inhibition, Ugi reaction
  • İstanbul Medipol Üniversitesi Adresli: Evet

Özet

DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.