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PROTACs- a game-changing technology

Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., Ter Brake, F., Essa, K. & Dömling, A., 2019, In : Expert Opinion on Drug Discovery. 14, 12, p. 1255-1268 14 p.

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Introduction: Proteolysis - targeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.
Original languageEnglish
Pages (from-to)1255-1268
Number of pages14
JournalExpert Opinion on Drug Discovery
Volume14
Issue number12
Early online date20-Sep-2019
Publication statusPublished - 2019

    Keywords

  • Degradation, PROTAC, structural analysis, article, chimera, clinical trial (topic), controlled study, crystal, drug efficacy, human, protein degradation, protein family, structure analysis, endogenous compound, proteasome, ubiquitin protein ligase

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