关键词： BTK CRBN PROTACs Pharmacokinetics Target protein degradation VHL

Mesh ： Acetamides / chemical synthesis chemistry pharmacokinetics pharmacology Adaptor Proteins, Signal Transducing / chemistry metabolism Adenine / analogs & derivatives chemistry metabolism Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors genetics metabolism B-Lymphocytes / cytology metabolism Binding Sites Cell Line Drug Design Half-Life Humans Ligands Molecular Docking Simulation Mutagenesis, Site-Directed Piperidines / chemistry metabolism Protein Structure, Tertiary Proteolysis / drug effects Ubiquitin-Protein Ligases / chemistry metabolism Von Hippel-Lindau Tumor Suppressor Protein / chemistry metabolism

来  源：   DOI：10.1016/j.bmcl.2019.126877   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
A new series of Proteolysis Targeting Chimeras (PROTACs) targeting Bruton\'s Tyrosine Kinase (BTK) was synthesized, with the goal of improving the pharmacokinetic properties of our previously reported PROTAC, MT802. We recently described the ability of MT802 to induce degradation of both wild-type and C481S mutant BTK in immortalized cells and patient-derived B-lymphocytes. However, the pharmacokinetic properties of MT802 were not suitable for further in vivo development. Therefore, we undertook a systematic medicinal chemistry campaign to overcome this issue and made a series of PROTACs with structural modifications to the linker and E3-recruiting ligand; more specifically, the new PROTACs were synthesized with different von Hippel-Lindau (VHL) and cereblon (CRBN) ligands while keeping the BTK ligand and linker length constant. This approach resulted in an equally potent PROTAC, SJF620, with a significantly better pharmacokinetic profile than MT802. This compound may hold promise for further in vivo exploration of BTK degradation.
摘要：
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