Abstract Inflammation is the common pathological basis of autoimmune diseases, metabolic diseases, malignant tumors, and other major chronic diseases. Inflammation plays an important role in tissue homeostasis. On one hand, inflammation can sense changes in the tissue environment, induce imbalance of tissue homeostasis, and cause tissue damage. On the other hand, inflammation can also initiate tissue damage repair and maintain normal tissue function by resolving injury and restoring homeostasis. These opposing functions emphasize the significance of accurate regulation of inflammatory homeostasis to ameliorate inflammation-related diseases. Potential mechanisms involve protein phosphorylation modifications by kinases and phosphatases, which have a crucial role in inflammatory homeostasis. The mechanisms by which many kinases resolve inflammation have been well reviewed, whereas a systematic summary of the functions of protein phosphatases in regulating inflammatory homeostasis is lacking. The molecular knowledge of protein phosphatases, and especially the unique biochemical traits of each family member, will be of critical importance for developing drugs that target phosphatases. Here, we provide a comprehensive summary of the structure, the “double-edged sword” function, and the extensive signaling pathways of all protein phosphatases in inflammation-related diseases, as well as their potential inhibitors or activators that can be used in therapeutic interventions in preclinical or clinical trials. We provide an integrated perspective on the current understanding of all the protein phosphatases associated with inflammation-related diseases, with the aim of facilitating the development of drugs that target protein phosphatases for the treatment of inflammation-related diseases. 

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Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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Small-Molecule PROTACs for Cancer Immunotherapy

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.

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

https://doi.org/10.1016/j.apsb.2022.09.022

Harnessing the cyclization strategy for new drug discovery

Type 2 diabetes mellitus (T2D) is a metabolic disorder that knows no boundaries and is spread across the globe. It is one of the most widely spread metabolic disorder, which has now been described as a 'lifestyle' disease. According to the recent study conducted by International Diabetes Federation, the number of diabetic patients will rise from 463 million to 700 million by the year 2045. Conventional therapies often fail to define clear parameters and did not provide early detection in case of diabetes and pre-diabetes. Due to the limitations associated with these therapies, inclination of research is now focused on developing methods or exploring pathways which can overcome these hurdles. Considering these factors, protein tyrosine phosphatase is considered as a promising molecular level legitimate therapeutic target and is known to negatively regulate leptin and insulin signaling pathways. It has shown to be effective in the management of diabetes mellitus in various in vitro and in vivo studies. Various PTP-1B inhibitors have been studied which had shown promising results in the management of diabetes mellitus and associated complications as well. These inhibitors act by increasing insulin sensitivity by inhibiting PTP-1B mediated insulin pathway. In this article we will review the underlying mechanism of protein tyrosine phosphatase and its inhibitors by various PTP 1-B inhibitors for the management of diabetes mellitus and will further throw some light on the challenges and development of these inhibitors. 

Exploring protein tyrosine phosphatases (PTP) and PTP-1B inhibitors in management of diabetes mellitus.

The protein tyrosine phosphatase SHP2 encoded by PTPN11 is a promising therapeutic target for cancer therapy, while the multifaceted roles of SHP2 complicate the drug discovery targeting SHP2. Given the biological significance of SHP2, strategies targeting SHP2 have been developed in recent years. To date, eight SHP2 inhibitors have advanced into clinical trials as mono- or combined therapy for treating solid tumors or adaptive resistant cancers. In this Perspective, we briefly summarize the strategies targeting SHP2 including inhibitors, activators, and proteolysis-targeting chimera (PROTAC) degraders. Besides, targeting the protein-protein interactions between SHP2 and other adaptor proteins is also discussed. Finally, we also highlight the target- and pathway-dependent combination strategies of SHP2 for cancer therapy. This Perspective may provide a timely and updated overview on the strategies targeting SHP2 for cancer therapy.

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.

Future Medicinal ChemistryVol. 14, No. 8 EditorialCombining EGFR inhibitors with SHP2 or LSD1 inhibitors to overcome multidrug resistance in cancerHuiqing Zhang, Xinyu Yang, Yihui Song & Bin YuHuiqing ZhangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, ChinaSearch for more papers by this author, Xinyu YangSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, ChinaSearch for more papers by this author, Yihui Song *Author for correspondence: Tel.: +86 0371 6778 1908; E-mail Address: songyihui@zzu.edu.cnhttps://orcid.org/0000-0001-7922-1209School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, ChinaSearch for more papers by this author & Bin Yu **Author for correspondence: E-mail Address: zzuyubin@hotmail.comhttps://orcid.org/0000-0002-7207-643XSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, ChinaSearch for more papers by this authorPublished Online:30 Mar 2022https://doi.org/10.4155/fmc-2021-0326AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: combination therapyEGFRLSD1multidrug resistanceSHP2References1. 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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download 

Yihui Song

Papers

Strategies Targeting Protein Tyrosine Phosphatase SHP2 for Cancer Therapy.

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

Harnessing the cyclization strategy for new drug discovery

Combining EGFR inhibitors with SHP2 or LSD1 inhibitors to overcome multidrug resistance in cancer.

Recent advances of LSD1/KDM1A inhibitors for disease therapy.