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Published on: November 9, 2020
Discovery of DCAF16-based PROTACs as SHP2 degraders
Xiaojing Pang1, Yuxin Gan1, Qingyuan Hu2
1Institute of Digital Materia Medica and Structural Pharmacology, Fujian Key Laboratory of Chinese Materia Medica, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Abstract:
The overexpression of SHP2 in various cancers establishes it as an attractive therapeutic target. Growing evidence indicates that the scaffold function of SHP2 contributes significantly to its oncogenic signaling and tumorigenesis. Unlike traditional inhibitors, PROTACs can simultaneously eliminate both the enzymatic and scaffold functions of the target protein, representing a more promising therapeutic strategy. Herein, we report the design and synthesis of SHP2 PROTACs that recruit the DCAF16 E3 ligase for targeted SHP2 degradation. Among which, SK8 exhibited the most potent anti-tumor activity. SK8 induced SHP2 degradation in a concentration- and time-dependent manner via the ubiquitin-proteasome system. Notably, under the tested experimental conditions, SK8 produced greater inhibition of cell proliferation, migration, and invasion, together with increased apoptosis, compared with SHP099. Preliminary mechanistic studies revealed that this enhanced potency stemmed from a more profound inhibition of RAS/MAPK and PI3K/AKT/mTOR signaling, coupled with the reversal of IFN-γ/JAK/STAT1 suppression. Overall, our findings support the potential of SHP2-targeted protein degradation as an alternative strategy to enzymatic inhibition and provide a promising starting point for the further development of SHP2 degraders.
Insights
New PROTACs targeting SHP2 (a protein tyrosine phosphatase) effectively degrade the protein, inhibiting cancer cell growth and metastasis. This protein degradation strategy shows promise over traditional enzyme inhibition for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- SHP2 (a protein tyrosine phosphatase) overexpression drives cancer progression through its enzymatic and scaffold functions.
- Targeting SHP2 is crucial for cancer therapy, but its dual functions pose challenges for traditional inhibitors.
- PROTACs offer a novel approach to simultaneously degrade target proteins, addressing both enzymatic and scaffold roles.
Purpose of the Study:
- To design and synthesize novel Proteolysis-Targeting Chimeras (PROTACs) for SHP2 degradation.
- To evaluate the anti-tumor efficacy of these SHP2 PROTACs.
- To investigate the underlying mechanisms of SHP2 PROTACs' anti-cancer activity.
Main Methods:
- Synthesis of novel SHP2-targeting PROTACs recruiting the DCAF16 E3 ligase.
- In vitro assessment of PROTAC-induced SHP2 degradation via the ubiquitin-proteasome system.
- Evaluation of anti-proliferative, anti-migratory, and pro-apoptotic effects in cancer cells.
- Analysis of downstream signaling pathways including RAS/MAPK, PI3K/AKT/mTOR, and IFN-γ/JAK/STAT1.
Main Results:
- The synthesized PROTAC SK8 demonstrated potent anti-tumor activity by inducing SHP2 degradation.
- SK8 significantly inhibited cancer cell proliferation, migration, and invasion while increasing apoptosis.
- SK8 outperformed the traditional inhibitor SHP099 in efficacy.
- Mechanistic studies revealed SK8's enhanced potency due to profound inhibition of oncogenic pathways and reversal of immune suppression pathways.
Conclusions:
- SHP2-targeted protein degradation via PROTACs is a viable and potent therapeutic strategy for cancer.
- SK8 represents a promising lead compound for developing novel SHP2 degraders.
- This approach offers advantages over traditional SHP2 enzymatic inhibition for cancer treatment.
