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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Small Molecule SHP2 Inhibitor LXQ-217 Affects Lung Cancer Cell Proliferation in Vitro and in Vivo
Hao Sun1, Xiaoyi Bai1, Yiting Zhang1
1State Key Laboratory of Microbial Technology, Shandong University, 266237, Qingdao, Shandong, P. R. China.
Background:
SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors.
Methods:
Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217.
Results:
An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs.
Conclusions:
Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.
Insights
LXQ-217, a novel SHP2 inhibitor, effectively suppressed lung cancer cell growth in vitro and in vivo. This uncharged orthosteric inhibitor shows promise as a safe and effective anti-lung cancer therapeutic agent.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- SHP2 phosphatase is highly expressed in various cancers, making it a potential therapeutic target.
- Developing SHP2 orthosteric inhibitors requires identifying uncharged pTyr mimics.
Purpose of the Study:
- To identify and characterize a novel SHP2 orthosteric inhibitor.
- To evaluate the anti-cancer efficacy of LXQ-217 in lung cancer models.
Main Methods:
- Surface plasmon resonance and cellular thermal shift assay for binding verification.
- Enzyme kinetics, cell viability, and colony formation assays for inhibition characterization.
- In vivo studies in nude mice to assess anti-lung cancer effects.
Main Results:
- LXQ-217, an electroneutral bromophenol derivative, acts as a competitive SHP2 inhibitor.
- LXQ-217 induced apoptosis and inhibited lung cancer cell growth by modulating RAS-ERK and PI3K-AKT pathways.
- Oral administration of LXQ-217 demonstrated significant inhibition of lung cancer proliferation in vivo with no observed toxicity.
Conclusions:
- LXQ-217 is a potent, uncharged orthosteric SHP2 inhibitor with demonstrated anti-lung cancer activity.
- These findings support the further development of LXQ-217 as a safe and effective anti-lung cancer drug.
