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Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design.
Krieger, Johannes; Sorrell, Fiona J; Wegener, Ansgar A; Leuthner, Birgitta; Machrouhi-Porcher, Fouzia; Hecht, Martin; Leibrock, Eva M; Müller, Juliane E; Eisert, Jonathan; Hartung, Ingo V; Schlesiger, Sarah.
Afiliação
  • Krieger J; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Sorrell FJ; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Wegener AA; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Leuthner B; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Machrouhi-Porcher F; Site Management Analytics, Merck KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Hecht M; Site Management Analytics, Merck KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Leibrock EM; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Müller JE; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Eisert J; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Hartung IV; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
  • Schlesiger S; Discovery and Development Technologies, Merck Healthcare KGaA, Frankfurter Straße 250, 64293, Darmstadt, Germany.
ChemMedChem ; 18(8): e202200615, 2023 04 17.
Article em En | MEDLINE | ID: mdl-36749883
ABSTRACT
Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for the first time a consistent data set which allows for direct comparison of structural variations including those which were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design a small library of highly potent BRD4-degraders comprising different VHL exit vectors. Newly designed degraders showed favorable molecular properties and significantly improved degradation potency compared to MZ1.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Proteína Supressora de Tumor Von Hippel-Lindau Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Nucleares / Proteína Supressora de Tumor Von Hippel-Lindau Idioma: En Revista: ChemMedChem Assunto da revista: FARMACOLOGIA / QUIMICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Alemanha
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