Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma

Chen, Xiaojing; Liu, Lu; Liu, Peng; Chen, Yingying; Lin, Dan; Yan, Hao; Qi, Yan; Wang, Yi; Qiu, Yinda; Fang, Bo; Huang, He Qing; Qian, Jianchang; Zhao, Yunjie; Du, Zhou; Zhang, Qianwen; Li, Xiaokun; Zheng, Xiaohui; Liu, Zhiguo

doi:10.1021/acs.jmedchem.1c01732

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…Additionally, platelets also have a great impact on the treatment of patients with osteosarcoma. For example, platelet-derived growth factor recepter can be used as a target for imatinib, mesylate, and other inhibitors in the treatment of osteosarcoma (44,45).…”

Section: Discussionmentioning

confidence: 99%

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics

et al. 2022

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BackgroundOsteosarcoma is a common metastatic tumor in children and adolescents. Because of its easy metastasis, patients often show a poor prognosis. Recently, researchers have found that platelets are closely related to metastasis of a variety of malignant tumors, but the role of platelets related characteristics in osteosarcoma is still unknown. The purpose of this study is to explore the characteristics of platelet-related subtypes and cell infiltration in tumor microenvironment.MethodsWe collected osteosarcoma cohorts from TCGA and GEO databases, and explored the molecular subtypes mediated by platelet-related genes and the related TME cell infiltration according to the expression of platelet-related genes in osteosarcoma. In addition, we also explored the differentially expressed genes (DEGs) among different molecular subtypes and established a protein-protein interaction network (PPI). Then we constructed a platelet scoring model by Univariate cox regression and least absolute shrinkage and selection operator (Lasso) cox regression model to quantify the characteristics of platelet in a single tumor. RT-PCR was used to investigate the expression of six candidate genes in osteosarcoma cell lines and normal osteoblast lines. Finally, we also predicted potential drugs with therapeutic effects on platelet-related subtypes.ResultsWe found that platelet-related genes (PRGs) can distinguish osteosarcoma into two different platelet-related subtypes, C1 and C2. And the prognosis of the C2 subtype was significantly worse than that of C1 subtype. The results of ESTIMATE analysis and GO/KEGG enrichment showed that the differences between different subtypes were mainly concentrated in immune response pathways, and the immune response of C2 was inhibited relative to C1. We further studied the relationship between platelet-related subtypes and immune cell infiltration. We found that the distribution of most immune cells in C1 subtype was higher than that in C2 subtype, and there was a correlation between C1 subtype and more immune cells. Finally, we screened the PRGs related to the prognosis of osteosarcoma through Univariate Cox regression, established independent prognostic platelet characteristics consisting of six genes to predict the prognosis of patients with OS, and predicted the drugs that may be used in the treatment of osteosarcoma. RT-PCR was used to verify the expression of candidate genes in osteosarcoma cells.ConclusionPlatelet scoring model is a significant biomarker, which is of great significance to determine the prognosis, molecular subtypes, characteristics of TME cell infiltration and therapy in patients with OS.

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Section: Discussionmentioning

confidence: 99%

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics

et al. 2022

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“…186 Another study demonstrated that PDGFRC was overexpressed in triple-negative breast cancer patients and was associated with the patients' survival. 187 Additionally, after PDGFC and its receptors are inhibited, the drug effect of doxorubicin (DOX) can be enhanced, with more tumor apoptosis than only using DOX. 187 Nayeem et al discovered that PDGFRα was overexpressed in prostate cancer and the phosphorylation of this molecule and its downstream effector such as Akt was associated with tumorigenesis.…”

Section: Disruption Of the Crosstalk Between Platelets And Cancersmentioning

confidence: 99%

“…187 Additionally, after PDGFC and its receptors are inhibited, the drug effect of doxorubicin (DOX) can be enhanced, with more tumor apoptosis than only using DOX. 187 Nayeem et al discovered that PDGFRα was overexpressed in prostate cancer and the phosphorylation of this molecule and its downstream effector such as Akt was associated with tumorigenesis. However, the PDGFRα/Akt axis can be inhibited by Imatinib, a tyrosine kinase inhibitor, suppressing the growth and metastasis of tumor cells.…”

Section: Disruption Of the Crosstalk Between Platelets And Cancersmentioning

confidence: 99%

“…For instance, it has been shown that in osteosarcoma, specific inhibition of PDGFRα/β kinases by pyrimidine‐2,4‐diamine derivatives can significantly kill tumor cell lines 186 . Another study demonstrated that PDGFRC was overexpressed in triple‐negative breast cancer patients and was associated with the patients’ survival 187 . Additionally, after PDGFC and its receptors are inhibited, the drug effect of doxorubicin (DOX) can be enhanced, with more tumor apoptosis than only using DOX 187 .…”

Section: Platelets and Cancer Treatmentmentioning

confidence: 99%

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The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy

Liao,

Zhang,

Liu

et al. 2023

MedComm

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Platelets are a class of pluripotent cells that, in addition to hemostasis and maintaining vascular endothelial integrity, are also involved in tumor growth and distant metastasis. The tumor microenvironment is a complex and comprehensive system composed of tumor cells and their surrounding immune and inflammatory cells, tumor‐related fibroblasts, nearby interstitial tissues, microvessels, and various cytokines and chemokines. As an important member of the tumor microenvironment, platelets can promote tumor invasion and metastasis through various mechanisms. Understanding the role of platelets in tumor metastasis is important for diagnosing the risk of metastasis and prolonging survival. In this study, we more fully elucidate the underlying mechanisms by which platelets promote tumor growth and metastasis by modulating processes, such as immune escape, angiogenesis, tumor cell homing, and tumor cell exudation, and further summarize the effects of platelet−tumor cell interactions in the tumor microenvironment and possible tumor treatment strategies based on platelet studies. Our summary will more comprehensively and clearly demonstrate the role of platelets in tumor metastasis, so as to help clinical judgment of the potential risk of metastasis in cancer patients, with a view to improving the prognosis of patients.

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“…Pharmacokinetic and In Vitro Metabolic StabilityStudy of Compound 5a. A preliminary pharmacokinetic (PK) study37 of compound 5a was performed by SAFE Pharmaceutical Technology Co., Ltd. (Beijing, China). BALB/ c mice were treated with compound 5a at doses of 5, 10, and 20 mg/kg body weight, and a 5a plasma concentration peaked 1 h after administration (Figure6A).…”

mentioning

confidence: 99%

A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

et al. 2022

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Quinazoline and its derivatives have drawn much attention in the development of potential antitumor agents. Here, we synthesized a series of 1,2,3-triazole derivatives of quinazoline at the C6 position and evaluated for their cytotoxic activity in various human cancer cell lines. We found that compound 5a was the most cytotoxic to HCT-116 cells (IC50, 0.36 μM). Target profiling found that 5a directly binds to both the autophagy-associated protein SQSTM1/P62 and the E3 ligase RNF168, promoting their interaction. Consistently, 5a treatment induces a decrease in RNF168-mediated H2A ubiquitination and compromises homologous recombination-mediated DNA repair, thus increasing the sensitivity of HCT-116 to X-ray radiation. Moreover, 5a suppressed xenografted tumor growth in mice in a dose-dependent manner. Taken together, the 1,2,3-triazole derivative of quinazoline 5a may serve as a novel compound for tumor therapy based on its role in promoting a P62/RNF168 interaction.

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Discovery of Potent and Orally Bioavailable Platelet-Derived Growth Factor Receptor (PDGFR) Inhibitors for the Treatment of Osteosarcoma

Cited by 8 publications

References 38 publications

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics

The role of platelets in the regulation of tumor growth and metastasis: the mechanisms and targeted therapy

A 1,2,3-Triazole Derivative of Quinazoline Exhibits Antitumor Activity by Tethering RNF168 to SQSTM1/P62

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