发现一类新型咪唑并吡嗪衍生物作为强效SHP2变构抑制剂
Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.
作者信息
Torrente Esther, Fodale Valentina, Ciammaichella Alina, Ferrigno Federica, Ontoria Jesus M, Ponzi Simona, Rossetti Ilaria, Sferrazza Alessio, Amaudrut Jérôme, Missineo Antonino, Esposito Simone, Palombo Simone, Nibbio Martina, Cerretani Mauro, Bisbocci Monica, Cellucci Antonella, di Marco Annalise, Alli Cristina, Pucci Vincenzo, Toniatti Carlo, Petrocchi Alessia
机构信息
Department of Drug Discovery IRBM S.p.A., Pomezia, Rome 00071, Italy.
Department of Biology and Translational Research, IRBM S.p.A., Pomezia, Rome 00071, Italy.
出版信息
ACS Med Chem Lett. 2023 Jan 10;14(2):156-162. doi: 10.1021/acsmedchemlett.2c00454. eCollection 2023 Feb 9.
Protein tyrosine phosphatase SHP2 is an oncogenic protein that can regulate different cytokine receptor and receptor tyrosine kinase signaling pathways. We report here the identification of a novel series of SHP2 allosteric inhibitors having an imidazopyrazine 6,5-fused heterocyclic system as the central scaffold that displays good potency in enzymatic and cellular assays. SAR studies led to the identification of compound , a highly potent SHP2 allosteric inhibitor. X-ray studies showed novel stabilizing interactions with respect to known SHP2 inhibitors. Subsequent optimization allowed us to identify analogue , which possesses excellent potency and a promising PK profile in rodents.
蛋白酪氨酸磷酸酶SHP2是一种致癌蛋白，可调节不同的细胞因子受体和受体酪氨酸激酶信号通路。我们在此报告了一系列新型的SHP2变构抑制剂的鉴定，这些抑制剂以咪唑并吡嗪[6,5-f]稠合杂环系统为核心骨架，在酶学和细胞实验中表现出良好的活性。构效关系（SAR）研究确定了化合物，一种高效的SHP2变构抑制剂。X射线研究表明，与已知的SHP2抑制剂相比，存在新的稳定相互作用。随后的优化使我们确定了类似物，其在啮齿动物中具有优异的活性和良好的药代动力学特性。
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