Crystallographic landscape of SHP2 provides molecular insights for SHP2 targeted drug discovery

IF 10.9 1区医学 Q1 CHEMISTRY, MEDICINAL

Medicinal Research Reviews Pub Date : 2022-05-16 DOI:10.1002/med.21890

Yihui Song, Xinyu Yang, Shu Wang, Min Zhao, Bin Yu

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引用次数: 11

Abstract

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy. The dynamic change of SHP2 between closed and open conformations under either physiological or pathological conditions provides opportunities to design SHP2 inhibitors for treating SHP2-related diseases. To date, several SHP2 allosteric inhibitors have advanced into clinical trials as mono- or combined therapy of cancers. In this review, we provide an overview on the structural landscape of SHP2 under physiological and pathological conditions and also comprehensively analyze the binding models of SHP2/inhibitor complexes. Structural features of SHP2 under pathological conditions and co-crystal structures of SHP2/inhibitor complexes will definitely facilitate structure-guided design of SHP2 inhibitors. Finally, proteolysis targeting chimeric (PROTAC) based SHP2 degraders have shown therapeutic promise for cancer therapy and are also briefly discussed. We hope this review could provide crystallographic landscape for SHP2 targeted drug discovery.

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SHP2的晶体景观为SHP2靶向药物的发现提供了分子视角

PTPN11编码的蛋白酪氨酸磷酸酶SHP2是一个很有前景的癌症治疗靶点。在生理或病理条件下，SHP2在封闭和开放构象之间的动态变化为设计治疗SHP2相关疾病的SHP2抑制剂提供了机会。迄今为止，几种SHP2变构抑制剂已进入临床试验，作为癌症的单一或联合治疗。本文综述了SHP2在生理和病理条件下的结构格局，并综合分析了SHP2/抑制剂复合物的结合模式。病理条件下SHP2的结构特征和SHP2/抑制剂复合物的共晶结构将为SHP2抑制剂的结构导向设计提供便利。最后，蛋白水解靶向嵌合(PROTAC)的SHP2降解物在癌症治疗中显示出治疗前景，并进行了简要讨论。我们希望本综述能为SHP2靶向药物的发现提供晶体学视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Medicinal Research Reviews 医学-药学

CiteScore

29.30

自引率

0.00%

发文量

审稿时长

2 months

期刊介绍： Medicinal Research Reviews is dedicated to publishing timely and critical reviews, as well as opinion-based articles, covering a broad spectrum of topics related to medicinal research. These contributions are authored by individuals who have made significant advancements in the field. Encompassing a wide range of subjects, suitable topics include, but are not limited to, the underlying pathophysiology of crucial diseases and disease vectors, therapeutic approaches for diverse medical conditions, properties of molecular targets for therapeutic agents, innovative methodologies facilitating therapy discovery, genomics and proteomics, structure-activity correlations of drug series, development of new imaging and diagnostic tools, drug metabolism, drug delivery, and comprehensive examinations of the chemical, pharmacological, pharmacokinetic, pharmacodynamic, and clinical characteristics of significant drugs.