苯基二氢尿嘧啶：用于PROTAC设计的一种替代性脑啡肽结合剂。
Phenyl Dihydrouracil: An Alternative Cereblon Binder for PROTAC Design.
作者信息
Jarusiewicz Jamie A, Yoshimura Satoshi, Mayasundari Anand, Actis Marisa, Aggarwal Anup, McGowan Kevin, Yang Lei, Li Yong, Fu Xiang, Mishra Vibhor, Heath Richard, Narina Shilpa, Pruett-Miller Shondra M, Nishiguchi Gisele, Yang Jun J, Rankovic Zoran
机构信息
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
出版信息
ACS Med Chem Lett. 2023 Jan 4;14(2):141-145. doi: 10.1021/acsmedchemlett.2c00436. eCollection 2023 Feb 9.
Thalidomide and its analogues are frequently used in PROTAC design. However, they are known to be inherently unstable, undergoing hydrolysis even in commonly utilized cell culture media. We recently reported that phenyl glutarimide (PG)-based PROTACs displayed improved chemical stability and, consequently, improved protein degradation efficacy and cellular potency. Our optimization efforts, aiming to further improve the chemical stability and eliminate the racemization-prone chiral center in PG, led us to the development of phenyl dihydrouracil (PD)-based PROTACs. Here we describe the design and synthesis of LCK-directing PD-PROTACs and compare their physicochemical and pharmacological properties to those of the corresponding IMiD and PG analogues.
沙利度胺及其类似物常用于PROTAC设计。然而，已知它们本质上不稳定，即使在常用的细胞培养基中也会发生水解。我们最近报道，基于苯基戊二酰亚胺（PG）的PROTAC显示出改善的化学稳定性，因此，提高了蛋白质降解效率和细胞活性。我们旨在进一步提高化学稳定性并消除PG中易发生外消旋化的手性中心的优化工作，促使我们开发了基于苯基二氢尿嘧啶（PD）的PROTAC。在此，我们描述了LCK导向的PD-PROTAC的设计与合成，并将它们的物理化学和药理性质与相应的免疫调节药物（IMiD）和PG类似物进行比较。
Zotero 插件