Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders

The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.

本研究首次设计并合成了针对苏氨酸酪氨酸激酶（TTK）的蛋白水解靶向嵌合体（PROTACs）。筛选得到活性最优的两个分子8e与8j，在COLO-205人结直肠癌细胞中展现出强效的TTK降解活性，其降解半数有效浓度（DC50）分别为1.7 nM与3.1 nM。该类化合物介导的蛋白酶体降解效应在洗脱处理后仍可维持约8小时。与结构相似的抑制剂类对照化合物8q、8r相比，降解剂8e与8j的抗增殖活性显著提升。此外，降解剂8e与8j还具备良好的药代动力学（PK）特征；在COLO-205人结直肠癌细胞异种移植瘤小鼠模型中，经腹腔注射（i.p.）给药后，二者可实现强效的靶点降解与体内抗肿瘤功效。