Enzymes of purine metabolism have potential utility as biological markers of normal lymphocytes and their neoplastic counterparts. The activity of two of them, methylthioadenosine phosphorylase (MTA phosphorylase) and purine nucleoside phosphorylase (PNP) were measured in peripheral mononuclear cells from 11 patients with B-chronic lymphocytic leukemia (B-CLL) and compared with those obtained in cells from 10 normal volunteers. An inverse relationship between the two phosphorylases was demonstrated in patients, with higher MTA-phosphorylase and lower PNP activities than in control subjects.
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Nucleobase analogue (NBA) drugs, such as 5-fluorouracil (5-FU), are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests that the use of S-methyl-5'-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential.
View Article and Find Full Text PDFAcute kidney injury (AKI) increases mortality risk and predisposes individuals to chronic kidney disease. Metabolic pathways play a crucial role in AKI pathophysiology. Here, we investigate the potential of methylthioadenosine phosphorylase (MTAP) inhibition as a novel renoprotective strategy in AKI.
View Article and Find Full Text PDFCell Rep Med
February 2025
Department of Orthopedic Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Bone Tumor Institution, Shanghai, China. Electronic address:
Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we identify a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a "cold" tumor microenvironment. MTAP-deleted OS relies on methionine metabolism and is sensitive to methionine intervention, achieved through either dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism.
View Article and Find Full Text PDFJ Med Chem
February 2025
Tango Therapeutics, 201 Brookline Ave, Boston, Massachusetts 02215, United States.
Deletion of the gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target -deleted cancer cells.
View Article and Find Full Text PDFJ Med Chem
February 2025
Medicinal Chemistry Department, Shanghai Haiyan Pharmaceutical Technology Co., Ltd., Pudong New Area, Shanghai 201203, China.
Synthetic lethality offers a robust strategy for discovering the next generation of precision medicine therapies tailored for molecularly defined patient populations. MAT2A inhibition is synthetically lethal in several cancers that exhibit a homozygous deletion of -methyl-5'-thioadenosine phosphorylase (MTAP). Herein, we report the identification of novel MAT2A inhibitors featuring a spiral ring to circumvent the C-N atropisomeric chirality utilizing structure-based drug design.
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