State Key Laboratory of Drug Research
State Key Laboratory of Drug Research
Yue X.,State Key Laboratory of Drug Research |
Ai J.,State Key Laboratory of Drug Research |
Xu Y.,Sun Yat Sen University |
Chen Y.,State Key Laboratory of Drug Research |
And 13 more authors.
Hepatology | Year: 2017
Deregulation of the immune system is believed to contribute to cancer malignancy, which has led to recent therapeutic breakthroughs facilitating antitumor immunity. In a malignant setting, immunoglobulin receptors, which are fundamental components of the human immune system, fulfill paradoxical roles in cancer pathogenesis. This study describes a previously unrecognized pro-oncogenic function of polymeric immunoglobulin receptor (pIgR) in the promotion of cell transformation and proliferation. Mechanistically, pIgR overexpression is associated with YES proto-oncogene 1, Src family tyrosine kinase (Yes) activation, which is required for pIgR-induced oncogenic growth. Specifically, pIgR activates the Yes-DNAX-activating protein of 12 kDa-spleen tyrosine kinase-Rac1/CDC42-MEK (extracellular signal-regulated kinase kinase)/ERK (extracellular signal-regulated kinase) cascade in an immunoreceptor tyrosine-based activating motif (ITAM)-dependent manner to promote cell transformation and tumor growth, although pIgR itself does not contain an ITAM sequence. Additionally, the combination of pIgR and phosphorylated Yes (p-Yes) levels serves as a prognostic biomarker for hepatitis B surface antigen-positive and early-stage hepatocellular carcinoma (HCC) patients. Moreover, pharmacological targeting of MEK/ERK or Yes represents a therapeutic option for the subgroup of patients with pIgR/p-Yes-positive HCC based on our results with both cancer cell-line-based xenografts and primary patient-derived xenografts. Conclusion: Our findings reveal the molecular mechanism by which pIgR promotes cancer malignancy, suggest the clinical potential of targeting this pathway in HCC, and provide new insight into the oncogenic role of immunoglobulin receptors. © 2017 by the American Association for the Study of Liver Diseases.
Hu H.-N.,State Key Laboratory of Drug Research |
Hu H.-N.,National Center for Drug Screening |
Zhou P.-Z.,CAS Shanghai Institute of Materia Medica |
Chen F.,State Key Laboratory of Drug Research |
And 5 more authors.
Acta Pharmacologica Sinica | Year: 2013
Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC 50 value=0.10±0.05 μmol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 μmol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 μmol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors. © 2013 CPS and SIMM.
Chai Q.,State Key Laboratory of Drug Research |
Shen Q.,CAS Shanghai Institute of Materia Medica |
Ma L.-P.,State Key Laboratory of Drug Research |
Wang X.,State Key Laboratory of Drug Research |
And 4 more authors.
Gaodeng Xuexiao Huaxue Xuebao/Chemical Journal of Chinese Universities | Year: 2011
The protein tyrosine phosphatases(PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurological disorders and diabetes. As part of a project aimed at identifying small molecular inhibitors based on PTPs family, focusing on diabetes mellitus, tumorigenesis, and infection, we performed the high-throughput screening(HTS) of a library of 48000 synthetic compounds for six representative PTPs, including PTP1B, SHP-1, SHP-2, PRL-3, CDC25B and LAR, and 3a, 4, 5, 9b-tetrahydro-3H-cyclopenta[c]quinoline analogues were identified as PTPs inhibitors. Keeping the core template complete, we began the modification of benzene ring, intending to find out the best modifying position in benzene ring and the proper amount of substitutions on it. Consequently, thirty-four compounds were designed and synthesized, and careful structure-activity relationship(SAR) study with respect to PTP1B, SHP-1, SHP-2, PRL-3, CDC25B and LAR was carried out. Finally, it was found that the compounds bearing a bulky substituent at 8-position of the cyclopentaquinoline acid turned out to be PTP1B inhibitors with good potency and selectivity against other assayed PTPs. The most potent PTP1B inhibitor in this series, compounds 31 and 35, show good activity(IC50=0.4 and 0.6 μmol/L, respectively) and excellent selectivity for PTP1B over SHP-1, SHP-2, PRL-3 and LAR, and 30-fold selectivity over CDC25B. Due to time limit, the modification of core template is not sufficient enough, and it would be the direction of our further work to discover more potent core structures.