Discovery of the First Examples of Threonine Tyrosine Kinase PROTAC Degraders.
J Med Chem
; 65(3): 2313-2328, 2022 02 10.
Article
in En
| MEDLINE
| ID: mdl-35084180
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
/
Proteolysis
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Year:
2022
Document type:
Article