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Hi-JAK-ing the ubiquitin system: The design and physicochemical optimisation of JAK PROTACs.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.bmc.2020.115326 Rishi R Shah 1 , Joanna M Redmond 2 , Andrei Mihut 2 , Malini Menon 2 , John P Evans 2 , John A Murphy 3 , Michelle A Bartholomew 2 , Diane M Coe 2
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.bmc.2020.115326 Rishi R Shah 1 , Joanna M Redmond 2 , Andrei Mihut 2 , Malini Menon 2 , John P Evans 2 , John A Murphy 3 , Michelle A Bartholomew 2 , Diane M Coe 2
Affiliation
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PROTACs have recently emerged as a novel paradigm in drug discovery. They can hijack existing biological machinery to selectively degrade proteins of interest, in a catalytic fashion. Here we describe the design, optimisation and biological activity of a set of novel PROTACs targeting the Janus kinase family (JAK1, JAK2, JAK3 and TYK2) of proximal membrane-bound proteins. The JAK family proteins display membrane localisation by virtue of their association with cytoplasmic tails of cytokine receptors, and there are no reports of a successful PROTAC strategy being deployed against this class of proteins. JAK PROTACs from two distinct JAK chemotypes were designed, optimising the physicochemical properties for each template to enhance cell permeation. These PROTACs are capable of inducing JAK1 and JAK2 degradation, demonstrating an extension of the PROTAC methodology to an unprecedented class of protein targets. A number of known ligase binders were explored, and it was found that PROTACs bearing an inhibitor of apoptosis protein (IAP) ligand induced significantly more JAK degradation over Von Hippel-Lindau (VHL) and Cereblon (CRBN) PROTACs. In addition, the mechanism of action of the JAK PROTACs was elucidated, and it was confirmed that JAK degradation was both IAP- and proteasome-dependent.
中文翻译：
Hi-JAK-泛素系统：JAK PROTAC的设计和理化优化。
PROTAC最近已成为一种新的药物发现范例。他们可以劫持现有的生物机械，以催化方式选择性降解目标蛋白质。在这里，我们描述了一组针对近端膜结合蛋白的Janus激酶家族（JAK1，JAK2，JAK3和TYK2）的新型PROTAC的设计，优化和生物学活性。JAK家族蛋白由于其与细胞因子受体的细胞质尾部相关联而显示出膜定位，并且没有报道针对这种蛋白部署成功的PROTAC策略的报道。设计了两种不同的JAK化学型的JAK PROTAC，优化了每种模板的理化特性，以增强细胞渗透性。这些PROTAC能够诱导JAK1和JAK2降解，展示了将PROTAC方法扩展到前所未有的蛋白质目标类别的方法。探索了许多已知的连接酶结合剂，发现带有凋亡蛋白（IAP）配体抑制剂的PROTAC诱导的JAK降解明显超过Von Hippel-Lindau（VHL）和Cereblon（CRBN）PROTAC。另外，阐明了JAK PROTAC的作用机理，并证实JAK降解是IAP和蛋白酶体依赖性的。
更新日期：2020-01-23
中文翻译：
Hi-JAK-泛素系统：JAK PROTAC的设计和理化优化。
PROTAC最近已成为一种新的药物发现范例。他们可以劫持现有的生物机械，以催化方式选择性降解目标蛋白质。在这里，我们描述了一组针对近端膜结合蛋白的Janus激酶家族（JAK1，JAK2，JAK3和TYK2）的新型PROTAC的设计，优化和生物学活性。JAK家族蛋白由于其与细胞因子受体的细胞质尾部相关联而显示出膜定位，并且没有报道针对这种蛋白部署成功的PROTAC策略的报道。设计了两种不同的JAK化学型的JAK PROTAC，优化了每种模板的理化特性，以增强细胞渗透性。这些PROTAC能够诱导JAK1和JAK2降解，展示了将PROTAC方法扩展到前所未有的蛋白质目标类别的方法。探索了许多已知的连接酶结合剂，发现带有凋亡蛋白（IAP）配体抑制剂的PROTAC诱导的JAK降解明显超过Von Hippel-Lindau（VHL）和Cereblon（CRBN）PROTAC。另外，阐明了JAK PROTAC的作用机理，并证实JAK降解是IAP和蛋白酶体依赖性的。
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