|
|
吡嗪类SHP2抑制剂的设计、合成及生物活性评价
|
Abstract:
SHP2是一个肿瘤治疗的潜在靶点。本文以TNO155为先导化合物，采用基于片段的药物设计策略，设计并合成三个系列共11个新型吡嗪类SHP2变构抑制剂，其结构均经1H-NMR和ESI-MS谱确证。采用荧光分析方法，通过替代底物DiFMUP的去磷酸化程度对目标化合物开展体外活性评价。结果表明，目标化合物对SHP2蛋白显示不同程度的抑制活性。其中2个化合物C-2和C-3的活性较为突出，值得进一步研究。
Eleven novel pyrazine SHP2 allosteric inhibitors were designed and synthesized in three series based on TNO155 of Novartis, drug design strategy based on fragments and molecular docking technology of computer-aided drug design. Their structures were confirmed by 1H-NMR and ESI-MS spectra. The in vitro activity of DiFMUP was evaluated by fluorescence analysis. The results showed that the target compounds showed different degrees of inhibitory activity on SHP2. Among them, two compounds, C-2 and C-3, have outstanding activity and deserve further study.
| [1] | Yuan, X.R., Bu, H., Zhou, J.P., et al. (2020) Recent Advances of SHP2 Inhibitors in Cancer Therapy: Current Development and Clinical Application. Journal of Medicinal Chemistry, 63, 11368-11396. https://doi.org/10.1021/acs.jmedchem.0c00249 |
| [2] | LaRochelle, J.R., Fodor, M., Vemulapalli, V., Mohseni, M., Wang, P., Stams, T., et al. (2018) Structural Reorganization of SHP2 by Oncogenic Mutations and Implications for Oncoprotein Resistance to Allosteric Inhibition. Nature Communications, 9, Article Number 4508. https://doi.org/10.1038/s41467-018-06823-9 |
| [3] | Scott, L.M., Lawrence, H.R., Sebti, S.M., et al. (2010) Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery. Current Pharmaceutical Design, 16, 1843-1862. https://doi.org/10.2174/138161210791209027 |
| [4] | Garcia Fortanet, J., Chen, C.H., Chen, Y.P., Chen, Z., Deng, Z., Firestone, B., et al. (2016) Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor. Journal of Medicinal Chemistry, 59, 7773-7782. https://doi.org/10.1021/acs.jmedchem.6b00680 |
| [5] | LaMarche, M.J., Acker, M., Argintaru, A., Bauer, D., Boisclair, J., Chan, H., et al. (2020) Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. Journal of Medicinal Chemistry, 63, 13578-13594. https://doi.org/10.1021/acs.jmedchem.0c01170 |
| [6] | Ma, C., Gao, P., Chu, J., et al. (2017) Novel Heterocyclic Derivatives Useful as SHP2 Inhibitors. WO2017211303A1. |
