Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors,ACS Medicinal Chemistry Letters

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Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2023-04-17 , DOI: 10.1021/acsmedchemlett.3c00059
Alessia Petrocchi ₁ , Alessandro Grillo ₂ , Luca Ferrante ₂ , Pietro Randazzo ₂ , Adolfo Prandi ₂ , Marilenia De Matteo ₂ , Costanza Iaccarino ₁ , Monica Bisbocci ₁ , Antonella Cellucci ₁ , Cristina Alli ₁ , Martina Nibbio ₁ , Vincenzo Pucci ₁ , Jérôme Amaudrut ₁ , Christian Montalbetti ₁ , Carlo Toniatti ₁ , Romano Di Fabio _{1,

2}

Affiliation

Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.

中文翻译：

一系列新型强效 SHP2 变构抑制剂的发现

含Src同源2的蛋白酪氨酸磷酸酶2（SHP2）是第一个报道的非受体致癌酪氨酸磷酸酶，连接多个信号转导级联并通过PD-1检查点受体发挥免疫抑制功能。作为旨在获得新型变构 SHP2 抑制剂的药物发现计划的一部分，鉴定了一系列在分子左侧区域带有原始双环[3.1.0]己烷碱性部分的吡唑吡嗪衍生物。我们在此报告了化合物25 （该系列中最有效的成员之一）的发现过程、体外药理学概况和早期可开发特征。

更新日期：2023-04-17

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