Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer

Zhang, Qiuyue; Fan, Zhongjiao; Zhang, Lianshan; You, Qidong; Wang, Lei

doi:10.1021/acs.jmedchem.1c00631

Cited by 25 publications

(14 citation statements)

References 202 publications

(427 reference statements)

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“…Some small molecules have been identified that allosterically activate PP2A directly and are termed small molecule activators of PP2A (SMAPs). 296 , 297 Phenothiazines and perphenazine were discovered to activate PP2A and dephosphorylate some of its targets, such as AKT. 298 , 299 Iterative rounds of synthesis and optimization have since led to the development of several SMAPs.…”

Section: Progress In Innovative Pharmacological Approaches That Targe...mentioning

confidence: 99%

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

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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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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Section: Progress In Innovative Pharmacological Approaches That Targe...mentioning

confidence: 99%

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

Pan

Zhou

Zhang

et al. 2022

Sig Transduct Target Ther

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“…Phosphorylation of proteins occurs most commonly at serines and threonines, where protein kinases transfer phosphate groups to these amino acid residues, usually using adenosine triphosphate as a substrate, and protein phosphatases hydrolyze phosphate from the amino acid residues of the protein. They collaborate to regulate protein function, stability, and signaling, as well as carrying out physiopathological tasks ( 85 ). Protein kinase C (PKC) isozymes are a group of serine/threonine kinases whose activity and levels are dispensed in several pathological heart conditions, including atherosclerosis (AS), myocardial infarction (MI), acute ischaemic, cardiac hypertrophy, cardiac arrhythmia, HF, and cardiac fibrosis ( 86 , 87 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Wang

Li²,

Sun³

et al. 2022

Front. Cardiovasc. Med.

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PurposeSodium-glucose cotransporter 2 (SGLT2) inhibitors have cardiorenal protective effects regardless of whether they are combined with type 2 diabetes mellitus, but their specific pharmacological mechanisms remain undetermined.Materials and MethodsWe used databases to obtain information on the disease targets of “Chronic Kidney Disease,” “Heart Failure,” and “Type 2 Diabetes Mellitus” as well as the targets of SGLT2 inhibitors. After screening the common targets, we used Cytoscape 3.8.2 software to construct SGLT2 inhibitors' regulatory network and protein-protein interaction network. The clusterProfiler R package was used to perform gene ontology functional analysis and Kyoto encyclopedia of genes and genomes pathway enrichment analyses on the target genes. Molecular docking was utilized to verify the relationship between SGLT2 inhibitors and core targets.ResultsSeven different SGLT2 inhibitors were found to have cardiorenal protective effects on 146 targets. The main mechanisms of action may be associated with lipid and atherosclerosis, MAPK signaling pathway, Rap1 signaling pathway, endocrine resistance, fluid shear stress, atherosclerosis, TNF signaling pathway, relaxin signaling pathway, neurotrophin signaling pathway, and AGEs-RAGE signaling pathway in diabetic complications were related. Docking of SGLT2 inhibitors with key targets such as GAPDH, MAPK3, MMP9, MAPK1, and NRAS revealed that these compounds bind to proteins spontaneously.ConclusionBased on pharmacological networks, this study elucidates the potential mechanisms of action of SGLT2 inhibitors from a systemic and holistic perspective. These key targets and pathways will provide new ideas for future studies on the pharmacological mechanisms of cardiorenal protection by SGLT2 inhibitors.

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“…Serine/threonine kinases (STKs), a group of approximately 125 protein kinases that phosphorylate serines or threonines, are capable of maintaining cellular homeostasis, regulating the cell signaling pathway, and participating in cell proliferation, apoptosis, and metabolism by phosphorylating nuclear effectors, transcription factors, and cell cycle regulators. [5][6][7][8] STK16 is a myristoylated and palmitoylated STK that participates in the regulation of a wide array of cellular processes. 9,10 Previous studies have indicated that STK16 knockdown or kinase inhibition leads to cytokinesis arrest, thus affecting cell growth and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Exosomes from M1‐polarized macrophages promote apoptosis in lung adenocarcinoma via the miR‐181a‐5p/ETS1/STK16 axis

Wang

Huang

et al. 2022

Cancer Science

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Serine/threonine kinase 16 (STK16) is crucial in on regulating tumor cell proliferation, apoptosis, and prognosis. Activated M1 macrophages regulate lung adenocarcinoma (LUAD) growth by releasing exosomes. This study aims to investigate the role of STK16 and then focus on the possible mechanisms through which exosomes derived from M1 macrophages play their roles in LUAD cells by targeting STK16. Clinical LUAD samples were used to evaluate the expression of STK16 and its association with prognosis. Exosomes were isolated from M0 and M1 macrophages by ultracentrifugation and were then identified by electron microscopy and western blotting. In vitro gain-and loss-of-function experiments with LUAD cells were performed to elucidate the functions of miR-181a-5p, ETS1, and STK16, and mouse xenograft models were used to verify the function of STK16 in vivo. Western blotting, quantitative real-time PCR, CCK-8 assay, cell apoptosis, immunohistochemistry staining, luciferase assay, ChIP assay, and bioinformatics analysis were performed to reveal the underlying mechanisms. High expression of STK16 was observed in LUAD tissues and cells, and higher expression of STK16 was associated with worse prognosis. Silencing STK16 expression inhibited cell proliferation and promoted apoptosis via the AKT1 pathway.Exosomes from M1 macrophages inhibited viability and promoted apoptosis by inhibiting STK16. Moreover, miR-181a-5p is the functional molecule in M1 macrophagederived exosomes and plays a vital role in inhibiting cell proliferation and promoting apoptosis by targeting ETS1 and STK16. Hence, exosomes derived from M1 macrophages were capable of inhibiting viability and promoting apoptosis in LUAD via the miR-181a-5p/ETS1/STK16 axis.

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Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer

Cited by 25 publications

References 202 publications

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

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

Mechanisms of Cardiorenal Protection With SGLT2 Inhibitors in Patients With T2DM Based on Network Pharmacology

Exosomes from M1‐polarized macrophages promote apoptosis in lung adenocarcinoma via the miR‐181a‐5p/ETS1/STK16 axis

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