In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA

Batool, Sidra; Nawaz, Muhammad Sulaman; Mushtaq, Gohar; Parvaiz, Fahed; Kamal, Mohammad Amjad

doi:10.1016/j.sjbs.2014.11.008

Cited by 7 publications

(5 citation statements)

References 24 publications

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“…Lomotrexol and AG2034 are GART inhibitors that reduce tumor growth but cause high toxicity [39]. Recently, new GART inhibitors, PY873, PY899, and DIA, have been developed but are yet to be evaluated for side-effects and toxicity [40]. Small molecule inhibitors, LSN3213128 and 326203-A, which target 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), a subunit of the ATIC enzyme, are being evaluated for treatment of triple-negative breast cancer [41].…”

Section: Discussionmentioning

confidence: 99%

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer

Agarwal

Chakravarthi

Behring

et al. 2020

Cancers

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The identification of colorectal cancer (CRC) molecular targets is needed for the development of drugs that improve patient survival. We investigated the functional role of phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), a de novo purine biosynthetic enzyme involved in DNA synthesis, in CRC progression and metastasis by using cell and animal models. Its clinical utility was assessed in human CRC samples. The expression of PAICS was regulated by miR-128 and transcriptionally activated by Myc in CRC cells. Increased expression of PAICS was involved in proliferation, migration, growth, and invasion of CRC cells irrespective of the p53 and microsatellite status. In mice, the depletion of PAICS in CRC cells led to reduced tumor growth and metastatic cell dissemination to the liver, lungs, and bone. Positron emission tomography imaging showed significantly reduced metastatic lesions in stable PAICS knockdown CRC cells. In cells with PAICS knockdown, there was upregulation of the epithelial mesenchymal transition marker, E-cadherin, and bromodomain inhibitor, JQ1, can target its increased expression by blocking Myc. PAICS was overexpressed in 70% of CRCs, and was associated with poor 5-year survival independent of the pathologic stage, patient’s race, gender, and age. Overall, the findings point to the usefulness of PAICS targeting in the treatment of aggressive colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer

Agarwal

Chakravarthi

Behring

et al. 2020

Cancers

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“…Taken these data together, this is a very intriguing question of whether it is possible to inhibit GART without a significant damage to healthy tissues. There are other new GART inhibitors including PY873, PY899, DIA [ 148 , 149 ] and compound 12 [ 150 ] and it would be interesting to see the results of the clinical trials.…”

Section: Pharmacological Targeting Of One-carbon Metabolism and Nuclementioning

confidence: 99%

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

et al. 2017

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Cancer-related metabolism has recently emerged as one of the "hallmarks of cancer". It has several important features, including altered metabolism of glucose and glutamine. Importantly, altered cancer metabolism connects different biochemical pathways into the one fine-tuned metabolic network, which stimulates high proliferation rates and plasticity to malignant cells. Among the keystones of cancer metabolism are one-carbon metabolism and nucleotide biosynthesis, which provide building blocks to anabolic reactions. Accordingly, the importance of these metabolic pathways for anticancer therapy has well been documented by more than fifty years of clinical use of specific metabolic inhibitors -methotrexate and nucleotides analogs. In this review we discuss one-carbon metabolism and nucleotide biosynthesis as common and specific features of many, if not all, tumors. The key enzymes involved in these pathways also represent promising anti-cancer therapeutic targets. We review different aspects of these metabolic pathways including their biochemistry, compartmentalization and expression of the key enzymes and their regulation at different levels. We also discuss the effects of known inhibitors of these pathways as well as the recent data on other enzymes of the same pathways as perspective pharmacological targets.

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“…However, extensive work continues with improving outlook. While side effects remain common, another GART inhibitor, AG2034, showed improved inhibition of tumor growth [97], and more recently developed inhibitors, PY873, PY899, and DIA have been under investigation [28,98,99]. To investigate other enzymes in the pathway, a virtual ligand screen of the National Cancer Institute Diversity compound set was used to identify a novel ATIC inhibitor, 326203-A.…”

Section: Outlook On Novel Purine-based Cancer Treatment Methodologiesmentioning

confidence: 99%

The Intersection of Purine and Mitochondrial Metabolism in Cancer

Vitto

Arachchige

Richardson

et al. 2021

Cells

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Nucleotides are essential to cell growth and survival, providing cells with building blocks for DNA and RNA, energy carriers, and cofactors. Mitochondria have a critical role in the production of intracellular ATP and participate in the generation of intermediates necessary for biosynthesis of macromolecules such as purines and pyrimidines. In this review, we highlight the role of purine and mitochondrial metabolism in cancer and how their intersection influences cancer progression, especially in ovarian cancer. Additionally, we address the importance of metabolic rewiring in cancer and how the evolving landscape of purine synthesis and mitochondria inhibitors can be potentially exploited for cancer treatment.

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In silico analysis of glycinamide ribonucleotide transformylase inhibition by PY873, PY899 and DIA

Cited by 7 publications

References 24 publications

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer

PAICS, a Purine Nucleotide Metabolic Enzyme, is Involved in Tumor Growth and the Metastasis of Colorectal Cancer

One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy

The Intersection of Purine and Mitochondrial Metabolism in Cancer

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