Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation

Wang, Peng-Hui; Jiang, Lulu; Cao, Yang; Zhang, Xiaodan; Chen, Bangjing; Zhang, Shiyu; Huang, Ke; Ye, Deyong; Zhou, Lu

doi:10.1016/j.bmc.2018.02.044

Cited by 24 publications

(26 citation statements)

References 30 publications

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“…Since PGAM1 was suggested as a potential therapeutic target for multiple cancer types, several PGAM1 inhibitors have been developed for cancer therapy. 21,22,28,[50][51][52][53] A summary of these inhibitors and their related functions are listed in Table 1. PGAM1 inhibitors are divided into pharmacological inhibitors and genetic inhibitors.…”

Section: Summary Of Pgam1 Inhibitors and Research Directions To Explomentioning

confidence: 99%

“…52 However, because of its multiple targets, its specificity to PGAM1 is poor. 28,54 Wang et al 53 used scaffold hopping and a sulfonamide reversal strategy based on the lead compound PGMI-004A to discover a series of xanthone derivatives (12a-12s) as novel PGAM1 inhibitors. These xanthone derivatives showed stronger efficacy and better specificity than PGMI-004A in the inhibition of PGAM1, as well as an increased anti-proliferative effect in the H1299 cell line.…”

Section: Summary Of Pgam1 Inhibitors and Research Directions To Explomentioning

confidence: 99%

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<p>Phosphoglycerate Mutase 1: Its Glycolytic and Non-Glycolytic Roles in Tumor Malignant Behaviors and Potential Therapeutic Significance</p>

Li¹,

Liu²

2020

OTT

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Phosphoglycerate mutase 1 (PGAM1) is an important enzyme that catalyzes the reversible conversion of 3-phosphoglycerate and 2-phosphoglycerate during the process of glycolysis. Increasing evidence suggests that PGAM1 is widely overexpressed in various cancer tissues and plays a significant role in promoting cancer progression and metastasis. Although PGAM1 is a potential target in cancer therapy, the specific mechanisms of action remain unknown. This review introduces the basic structure and functions of PGAM1 and its family members and summarizes recent advances in the role of PGAM1 and various inhibitors of cancer cell proliferation and metastasis from a glycolytic and non-glycolytic perspective. Recent studies have highlighted a correlation between PGAM1 and clinical features and prognosis of cancer as well as the development of target drugs for PGAM1. The integrated information in this review will help better understand the specific roles of PGAM1 in cancer progression. Furthermore, the information highlights the non-glycolytic functions of PGAM1 in tumor metastasis, providing an innovative basis and direction for clinical drug research.

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Section: Summary Of Pgam1 Inhibitors and Research Directions To Explomentioning

confidence: 99%

Section: Summary Of Pgam1 Inhibitors and Research Directions To Explomentioning

confidence: 99%

<p>Phosphoglycerate Mutase 1: Its Glycolytic and Non-Glycolytic Roles in Tumor Malignant Behaviors and Potential Therapeutic Significance</p>

Li¹,

Liu²

2020

OTT

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“…Foregoing investigations revealed that PGMI-004A inhibits the PGAM1 activity via directly binding at its catalytic site. 48 Moreover, treatment of PGMI-004A significantly decreased the tumor growth in vivo. Authors declared that PGMI-004A by specifically targeting PGAM1 induced specific toxicity in cancer cells in vivo as well as in primary leukemia cells from cancer patients with no off target effects.…”

Section: Pharmacological Inhibitors Of Pgam1mentioning

confidence: 96%

“…Sulfonamide PGMI‐004A is a structural modification of ARS, by addition of hydrophobic groups through a sulfonamide bond, possibly reduces the cell proliferation in vitro. Foregoing investigations revealed that PGMI‐004A inhibits the PGAM1 activity via directly binding at its catalytic site . Moreover, treatment of PGMI‐004A significantly decreased the tumor growth in vivo.…”

Section: Pharmacological Inhibitors Of Pgam1mentioning

confidence: 99%

“…Moreover, treatment of PGMI‐004A significantly decreased the tumor growth in vivo. Authors declared that PGMI‐004A by specifically targeting PGAM1 induced specific toxicity in cancer cells in vivo as well as in primary leukemia cells from cancer patients with no off target effects . Later on the reversal strategy for sulfonamide was used to make a series of xanthone derivatives that switched the anthraquinone core of PGMI‐004A with xanthone core, which showed 26 times inhibitory efficacy than PGMI‐004A (Figure ).…”

Section: Pharmacological Inhibitors Of Pgam1mentioning

confidence: 99%

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Phosphoglycerate mutase 1 in cancer: A promising target for diagnosis and therapy

et al. 2019

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Altered enzymatic machineries are a substantial biochemical characteristic of tumor cell metabolism that switch metabolic profile from oxidative phosphorylation to amplified glycolysis as well as increased lactate production under hypoxia conditions. Reprogrammed metabolic profile is an emerging hallmark of cancer. Overexpression of several glycolytic enzymes and glucose transporters has been reported in 24 different types of cancers that represent approximately 70% of all the cancer cases around the globe. Thus, targeting glycolytic enzymes could serve as tempting avenue for drug design against cancer. Phosphoglycerate mutase 1 (PGAM1) is an important glycolytic enzyme that catalyzes the conversion of 3‐phosphoglycerate to 2‐phosphoglycerate. Recent investigations have revealed the overexpression of PGAM1 in several human cancers that is linked with tumor growth, survival, and invasion. The aim of this review is to update scientific research network with cancer‐specific role of PGAM1 to elucidate its capability as bonafide therapeutic target for cancer therapy. Moreover, we have also summarized the reported genetic and pharmacological inhibitors of PGAM1. This study suggests that further investigations on PGAM1 should focus on the exploration of molecular mechanisms of PGAM1 overexpression in development of cancer, assessment of biosafety profiles of known inhibitors of PGAM1, and utilization of PGAM1 inhibitors in combinatorial therapies. These future studies will surely support the unbiased strategies for the development of novel PGAM1 inhibitors for cancer therapies.

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Phosphoglycerate mutase 1 that is essential for glycolysis may act as a novel metabolic target for predicating poor prognosis for patients with gastric cancer

Chen

Xie

Yuan

et al. 2022

Clinical Laboratory Analysis

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Background: To identify a novel marker for gastric cancer, we examined the usefulness of phosphoglycerate mutase 1 (PGAM1) as a potential diagnostic marker using isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics and evaluated its clinical significance.Methods: Proteins from a discovery group of four paired gastric cancer tissues and adjacent gastric tissues were labeled with iTRAQ reagents and then identified and quantified using LC-MS/MS. The expression of PGAM1 was further validated in 139 gastric cancer patients using immunohistochemistry. Furthermore, the correlation of PGAM1 expression with clinical parameters was analyzed. Gene set enrichment analysis (GSEA) was performed to identify gene sets that were activated in PGAM1overexpressing patients with gastric cancer.Results: PGAM1 was significantly overexpressed in most cancers but particularly so in gastric cancer, with a sensitivity of 82.01% (95% confidence interval [CI]: 75.5%-88.5%) and specificity of 79.13% (95% CI: 72.3%-86%). Its expression was significantly associated with histological grade II and III tumors (p = 0.033), lymph node metastasis (p = 0.031), and TNM III-IV staging (p = 0.025). The area under the receiver operating characteristic (ROC) curve for the detection of PGAM1 overexpression in gastric cancer was 0.718 (p < 0.01). Furthermore, GSEA revealed that several important pathways such as glycolysis pathway and immune pathways were significantly enriched in patients with gastric cancer with PGAM1 overexpression. Conclusions:This study provided a sensitive method for detecting PGAM1, which may serve as a novel indicator for poor prognosis of gastric cancer, as well as a potent drug target for gastric cancer.

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Xanthone derivatives as phosphoglycerate mutase 1 inhibitors: Design, synthesis, and biological evaluation

Cited by 24 publications

References 30 publications

<p>Phosphoglycerate Mutase 1: Its Glycolytic and Non-Glycolytic Roles in Tumor Malignant Behaviors and Potential Therapeutic Significance</p>

<p>Phosphoglycerate Mutase 1: Its Glycolytic and Non-Glycolytic Roles in Tumor Malignant Behaviors and Potential Therapeutic Significance</p>

Phosphoglycerate mutase 1 in cancer: A promising target for diagnosis and therapy

Phosphoglycerate mutase 1 that is essential for glycolysis may act as a novel metabolic target for predicating poor prognosis for patients with gastric cancer

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