Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family

Freidman, Natasha; Briot, Chelsea; Ryan, Renae M.

doi:10.1016/j.jbc.2022.102178

Cited by 8 publications

(3 citation statements)

References 62 publications

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“…Small-molecule inhibitors of SLC1A5, derived from amino acid substrates, have been previously identified, including examples that were initially mischaracterized as SLC1A5 inhibitors, such as V-9302 [69]. Moreover, there are purported SLC1A5 agents that demonstrate broad inhibition across SLC family transporters and/or other off-target effects, which may obfuscate interpretation regarding how SLC1A4 or SLC1A5 contribute to pathophysiologic processes [69][70][71][72][73][74]. Such example reports accentuate the importance of full pharmacologic characterization of small-molecule inhibitors across the SLC glutamine transporters.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2)

Lyda,

Leary,

Farnsworth

et al. 2024

Molecules

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As a conformationally restricted amino acid, hydroxy-l-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened synthetic hydroxy-l-proline derivatives using electrophysiological and radiolabeled uptake methods against amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We have discovered a novel class of alkoxy hydroxy-pyrrolidine carboxylic acids (AHPCs) that act as selective high-affinity inhibitors of the SLC1 family neutral amino acid transporters SLC1A4 and SLC1A5. AHPCs were computationally docked into a homology model and assessed with respect to predicted molecular orientation and functional activity. The series of hydroxyproline analogs identified here represent promising new agents to pharmacologically modulate SLC1A4 and SLC1A5 amino acid exchangers which are implicated in numerous pathophysiological processes such as cancer and neurological diseases.

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Section: Discussionmentioning

confidence: 99%

Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2)

Lyda,

Leary,

Farnsworth

et al. 2024

Molecules

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“…GPNA can inhibit ASCT2 and other glutamine transporters, such as sodium-coupled neutral amino acid transporter 1 (SNAT1), SNAT2, large neutral amino acid transporter 1 (LAT1), and LAT2, leading to decreased uptake of essential amino acids ( Bröer et al, 2016 ; Chiu et al, 2017 ). The antitumor activity of GPNA may also be attributed to the interaction with excitatory amino acid transporters (EAATs) and substantial disruption of intracellular chloride or water homeostasis ( Freidman et al, 2022 ). Corti et al indicated that GPNA can be hydrolyzed by γ-glutamyltransferase (GGT) to produce p-nitroaniline (PNA), reducing the viability of lung cancer A549 cells without decreased cellular glutamine uptake ( Corti et al, 2019 ).…”

Section: Drugs Targeting Glutamine Metabolism For Cancer Treatmentmentioning

confidence: 99%

Exploiting the Achilles’ heel of cancer: disrupting glutamine metabolism for effective cancer treatment

Fan,

Xue,

et al. 2024

Front. Pharmacol.

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Cancer cells have adapted to rapid tumor growth and evade immune attack by reprogramming their metabolic pathways. Glutamine is an important nitrogen resource for synthesizing amino acids and nucleotides and an important carbon source in the tricarboxylic acid (TCA) cycle and lipid biosynthesis pathway. In this review, we summarize the significant role of glutamine metabolism in tumor development and highlight the vulnerabilities of targeting glutamine metabolism for effective therapy. In particular, we review the reported drugs targeting glutaminase and glutamine uptake for efficient cancer treatment. Moreover, we discuss the current clinical test about targeting glutamine metabolism and the prospective direction of drug development.

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“… Strategy Drug target Drug used Mechanism of action Ref. Glutamine depletion Glutamine l -asparaginase Erwinaze Catalyzes the hydrolysis of asparagine and glutamine, depleting these amino acids and inhibiting cancer cell survival and proliferation [ 81 , 89 ] Glutaminase inhibitors GLS1 CB-839 BPTES Compound 968 Inhibiting GLS function, reducing Gln utilization and its flux into the TCA cycle [ 90 – 92 ] Glutamine antagonists/ analogs Glutamine DON Irreversibly competing with Gln for enzymes’ binding site [ 93 ] Glutamine uptake inhibitors SLC1A5 GPNA V-9302 (GPNA derivative) Inhibiting glutamine transport by binding to SLC1A5 [ 94 , 95 ] BPTES Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, DON 6-diazo-5-oxo- l -norleucine, Gln glutamine, GLS glutaminase, GPNA L-c-glutamyl-p-nitroanilide, TCA tricarboxylic acid. …”

Section: Interplay Between Autophagy and Amino Acids Metabolism In Am...mentioning

confidence: 99%

Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia

Chen,

Zou

et al. 2024

Cell Death Discov.

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Acute myeloid leukemia (AML), a prevalent form of leukemia in adults, is often characterized by low response rates to chemotherapy, high recurrence rates, and unfavorable prognosis. A critical barrier in managing refractory or recurrent AML is the resistance to chemotherapy. Increasing evidence indicates that tumor cell metabolism plays a crucial role in AML progression, survival, metastasis, and treatment resistance. Autophagy, an essential regulator of cellular energy metabolism, is increasingly recognized for its role in the metabolic reprogramming of AML. Autophagy sustains leukemia cells during chemotherapy by not only providing energy but also facilitating rapid proliferation through the supply of essential components such as amino acids and nucleotides. Conversely, the metabolic state of AML cells can influence the activity of autophagy. Their mutual coordination helps maintain intrinsic cellular homeostasis, which is a significant contributor to chemotherapy resistance in leukemia cells. This review explores the recent advancements in understanding the interaction between autophagy and metabolism in AML cells, emphasizing their roles in cell survival and drug resistance. A comprehensive understanding of the interplay between autophagy and leukemia cell metabolism can shed light on leukemia cell survival strategies, particularly under adverse conditions such as chemotherapy. This insight may also pave the way for innovative targeted treatment strategies.

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Characterizing unexpected interactions of a glutamine transporter inhibitor with members of the SLC1A transporter family

Cited by 8 publications

References 62 publications

Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2)

Discovery and Synthesis of Hydroxy-l-Proline Blockers of the Neutral Amino Acid Transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2)

Exploiting the Achilles’ heel of cancer: disrupting glutamine metabolism for effective cancer treatment

Crosstalk between autophagy and metabolism: implications for cell survival in acute myeloid leukemia

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