Journal
BIOORGANIC CHEMISTRY
Volume 110, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.104788
Keywords
SHP2; PROTAC; Protein degrader
Funding
- National Natural Science Foundation of China (NSFC) [81773594, 81903863, U1703111, U1803122, 81773637]
- National Mega-project for Innovative Drugs [2019ZX09721001-004-007]
- China Postdoctoral Science Foundation [2019M652661]
- Chunhui Program-Cooperative Research Project of the Ministry of Education
- Liaoning Province Natural Science Foundation [2020-MZLH-31, 2019-MS-299]
- Liaoning Revitalization Talents Program [XLYC1807182]
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The study introduces a method to target SHP2 using CRBN-recruiting PROTAC molecules, with SP4 showing significant inhibition of growth in Hela cells and the ability to induce SHP2 degradation and cell apoptosis. Further research on SHP2-protac may hold important implications for treating SHP2-related diseases.
Protein tyrosine phosphatase SHP2 is a member of PTPs family associated with cancer such as leukemia, nonsmall cell lung cancer, breast cancer, and so on. SHP2 is a promising target for drug development, and consequently it is of great significance to develop SHP2 inhibitors. Herein, we report CRBN-recruiting PROTAC molecules targeting SHP2 by connecting pomalidomide with SHP099, an allosteric inhibitor of SHP2. Among them, SP4 significantly inhibited the growth of Hela cells, compared with SHP099, its activity increased 100 times. In addition, it can significantly induce SHP2 degradation and cell apoptosis. Further study of SHP2-protac may have important significance for the treatment of SHP2 related diseases.
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