Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders
Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders
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DOI：
10.1021/acs.jmedchem.1c01768
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发表时间：
2022-02-10
影响因子：
7.3
通讯作者：
Ding，Ke
中科院分区：
文献类型：
--
作者：
Lu，Jibu;Huang，Yongjun;Ding，Ke
设计并合成了第一个苏氨酸酪氨酸激酶 (TTK) PROTAC 实例。两种最有效的分子 8e 和 8j 在 COLO-205 人结直肠癌细胞中表现出强烈的 TTK 降解作用，DC50 值分别为 1.7 和 3.1 nM。清洗后，蛋白酶体介导的化合物降解可持续约 8 小时。与结构相似的抑制剂对应物8q和8r相比，降解剂8e和8j表现出改善的抗增殖活性。 Degraders8e 和 8j 还表现出合理的 PK 曲线，并在 COLO-205 人结直肠癌细胞的异种移植小鼠模型中显示出有效的目标降解和体内抗癌功效。行政。
The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules,8eand8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders8eand8jdemonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts8qand8r. Degraders8eand8jalso demonstrated reasonable PK profiles and exhibited potent target degradation andin vivoanticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.