Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein
- 21 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (14), 7510-7528
- https://doi.org/10.1021/acs.jmedchem.0c00471
Abstract
Src homology 2 domain-containing phosphatase 2 (SHP2) is an attractive therapeutic target for human cancers and other human diseases. Herein, we report our discovery of potent small-molecule SHP2 degraders whose design is based upon the proteolysis-targeting chimera (PROTAC) concept. This work has led to the discovery of potent and effective SHP2 degraders, exemplified by SHP2-D26. SHP2-D26 achieves DC50 values of 6.0 and 2.6 nM in esophageal cancer KYSE520 and acute myeloid leukemia MV4;11 cells, respectively, and is capable of reducing SHP2 protein levels by >95% in cancer cells. SHP2-D26 is >30-times more potent in inhibition of phosphorylation of extracellular signal-regulated kinase (ERK) and of cell growth than SHP099, a potent SHP2 inhibitor, in KYSE520 and MV4;11 cancer cell lines. This study demonstrates that induced SHP2 degradation is a very effective approach to inhibit the function of SHP2. Further optimization of these SHP2 degraders may lead to the development of a new class of therapies for cancers and other human diseases.Keywords
Funding Information
- National Cancer Institute (P30 CA046592)
- Oncopia Therapeutics Inc
This publication has 62 references indexed in Scilit:
- Tyrosine phosphatase SHP2 promotes breast cancer progression and maintains tumor-initiating cells via activation of key transcription factors and a positive feedback signaling loopNature Medicine, 2012
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- The tyrosine phosphatase Shp2 (PTPN11) in cancerCancer and Metastasis Reviews, 2008
- Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumorsOncogene, 2008
- PTPN11 (Shp2) Mutations in LEOPARD Syndrome Have Dominant Negative, Not Activating, EffectsOnline Journal of Public Health Informatics, 2006
- Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous LeukemiaCancer Research, 2004
- Molecular Mechanism for a Role of SHP2 in Epidermal Growth Factor Receptor SignalingMolecular and Cellular Biology, 2003
- Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemiaNature Genetics, 2003
- Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathwayNature, 2002
- Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndromeNature Genetics, 2001