Allosteric Inhibitors of SHP2 with Therapeutic Potential for Cancer Treatment
| Autor: | Jingjing Xie, Xiaojia Si, Shoulai Gu, Mingliang Wang, Jian Shen, Haoyan Li, Dan Li, Yanjia Fang, Cong Liu, Jidong Zhu |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cell signaling MAP Kinase Signaling System T cell Allosteric regulation BTLA Administration Oral Mice Nude Antineoplastic Agents Protein Tyrosine Phosphatase Non-Receptor Type 11 Naphthalenes Crystallography X-Ray 03 medical and health sciences Inhibitory Concentration 50 Structure-Activity Relationship 0302 clinical medicine Allosteric Regulation Piperidines Drug Discovery medicine Animals Humans Enzyme Inhibitors Adaptor Proteins Signal Transducing Cell Proliferation Mice Inbred BALB C Binding Sites Chemistry Cancer YAP-Signaling Proteins medicine.disease Phosphoproteins Xenograft Model Antitumor Assays Immune checkpoint Cell biology Thiazoles 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer cell Mutation Molecular Medicine Female Drug Screening Assays Antitumor Transcription Factors |
| Zdroj: | Journal of medicinal chemistry. 60(24) |
| ISSN: | 1520-4804 |
| Popis: | SHP2, a cytoplasmic protein-tyrosine phosphatase encoded by the PTPN11 gene, is involved in multiple cell signaling processes including Ras/MAPK and Hippo/YAP pathways. SHP2 has been shown to contribute to the progression of a number of cancer types including leukemia, gastric, and breast cancers. It also regulates T-cell activation by interacting with inhibitory immune checkpoint receptors such as the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA). Thus, SHP2 inhibitors have drawn great attention by both inhibiting tumor cell proliferation and activating T cell immune responses toward cancer cells. In this study, we report the identification of an allosteric SHP2 inhibitor 1-(4-(6-bromonaphthalen-2-yl)thiazol-2-yl)-4-methylpiperidin-4-amine (23) that locks SHP2 in a closed conformation by binding to the interface of the N-terminal SH2, C-terminal SH2, and phosphatase domains. Compound 23 suppresses MAPK signaling pathway and YAP transcriptional activity and shows antitumor activity in vivo. The results indicate that allosteric inhibition of SHP2 could be a feasible approach for cancer therapy. |
| Databáze: | OpenAIRE |
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