Discovery of <i>N</i>-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3<i>R</i>)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model

Fales, Kevin R.; Njoroge, F. George; Brooks, Harold B.; Thibodeaux, Stefan Jon; Torrado, Alicia; Si, Chong; Toth, John E.; Cowan, Jefferson R. Mc; Roth, Kenneth D.; Thrasher, K. Jeff; Frimpong, Kwame; Lee, Matthew R.; Dally, Robert; Shepherd, Timothy A.; Durham, Timothy B.; Margolis, Brandon J.; Wu, Ziping; Wang, Yong; Atwell, S.; Wang, Jing; Hui, Yu‐Hua; Meier, Timothy I.; Konicek, S A; Geeganage, Sandaruwan

doi:10.1021/acs.jmedchem.7b01046

Cited by 29 publications

(20 citation statements)

References 42 publications

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“…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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“…Thus, the use of certain antifolates as inhibitors of these two enzymes have been demonstrated to be another way to disrupt the normal DNA synthesis in highly multiplying cells. Some non-classical antifolates have been synthesized and successfully inhibit tumor growth both in vitro and in vivo [25,26]. However, this approach cannot be applied for P. falciparum infections because it lacks of the necessary enzymes for the de novo purine synthesis [27].…”

Section: Mechanisms Of Action Of Antifolatesmentioning

confidence: 99%

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Fernández‐Villa

Aguilar

Rojo

2019

IJMS

137

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Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications.

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“…This compound was demonstrated to be capable of binding a subunit AICAR transformylase (AICARFT) of ATIC [100]. Similarly, significant growth inhibition by another novel AICARFT inhibitor, LSN3213128 has been observed in xenograft breast and lung cancer models [101]. The overexpression of PAICS is common to many forms of cancer and recognized as a potential target for inhibition [34,102,103].…”

Section: Outlook On Novel Purine-based Cancer Treatment Methodologiesmentioning

confidence: 95%

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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Cited by 29 publications

References 42 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

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

The Intersection of Purine and Mitochondrial Metabolism in Cancer

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