Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 3, Pages 2313-2328Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01768
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Funding
- Natural Science Foundation of China [81820108029, 81874284, 22037003, 22077050, 81800774, 81973158]
- Ministry of Science and Technology [SQ2019YFE010401]
- Guangdong Province [2018B030337001, 2019A1515011235]
- Guangzhou City [202002030414]
- State Key Laboratory of Bioorganic Chemistry and Nature Products, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
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The first examples of threonine tyrosine kinase (TTK) PROTACs were successfully designed and synthesized, showing strong degradation effects in human colorectal cancer cells and potential anticancer activities.
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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