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Published on: November 9, 2020
Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders
Jibu Lu1,2, Yongjun Huang3, Jing Huang3
1Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, China.
Abstract:
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.
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