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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Design, synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties
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Design, synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties

机译：靶向嵌合体（Protacs）的设计，合成及生物学评价为具有改进的药代动力学性能的BTK降解剂

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摘要

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.
机译：合成了一种新的蛋白分解靶向嵌合嵌合体（Protacs）的嵌合体（PROTAC），其综合了靶向酪氨酸激酶（BTK），目的是改善我们先前报道的PROTAC的药代动力学性质MT802。我们最近描述了MT802在永生化细胞和患者衍生的B淋巴细胞中诱导野生型和C481S突变体BTK的降解的能力。然而，MT802的药代动力学特性不适合于体内发育。因此，我们进行了系统的药用化学活动，以克服这一问题，并制作了一系列具有结构修饰的Protac和E3招募配体;更具体地，使用不同的von Hippel-Lindau（VHL）和酰胺（CRBN）配体合成新的斑块，同时保持BTK配体和接头长度恒定。该方法导致同样有效的Protac SJF620，其具有比MT802更优选更好的药代动力学曲线。该化合物可以在体内探索BTK降解中进一步持有该化合物。

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