期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 218, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113341
关键词
SHP2 degradation; Proteolysis targeting chimera (PROTAC); Thalidomide-based heterobifunctional molecules; E3 ubiquitin ligase; CRBN
资金
- National Natural Science Foundation of China [81973166, 21702218, 21772068, 81773779, 81773568, 91753207]
- National Science and Technology Major Project of China [2018ZX09711002-008-004, 2018ZX09711002-008-005, 2018ZX09711002-006-001]
- K. C. Wong Education Foundation
- Youth innovation promotion association [2017333]
SHP2, a non-receptor tyrosine phosphatase, plays a crucial role in various oncogenic cell signaling cascades. PROTAC has emerged as a promising strategy for degrading disease-related proteins. Through the design and evaluation of a series of thalidomide-based heterobifunctional molecules, a highly efficient SHP2 degrader was identified, providing a new strategy for SHP2-mediated cancer therapy.
SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation. (c) 2021 Elsevier Masson SAS. All rights reserved.
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