2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport

Schulte, M.; Khodadadi, Alexandra B.; Cuthbertson, Madison L.; Smith, Jarrod A.; Manning, H. Charles

doi:10.1016/j.bmcl.2015.12.031

Cited by 54 publications

(57 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, as cell surface molecules, these transporters may be more readily druggable. Accordingly, novel inhibitors of SLC1A5 have recently been described (54). In addition, several groups are evaluating glutamine analogs for their value in positron emission tomography (PET) imaging of cancer (55).…”

Section: Discussionmentioning

confidence: 99%

Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer

White

Lin

Rajapakshe

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Despite the known importance of androgen receptor (AR) signaling in prostate cancer (PCa), the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in PCa cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in PCa. Correspondingly, gene expression signatures of AR activity correlated with SLC1A4 and SLC1A5 mRNA levels in clinical cohorts. Interestingly, MYC, a canonical oncogene in PCa and previously described master regulator of glutamine metabolism, was only a context-dependent regulator of SLC1A4 and SLC1A5 levels, being unable to regulate either transporter in phosphatase and tensin homolog (PTEN) wild-type cells. In contrast, rapamycin was able to decrease the androgen-mediated expression of SLC1A4 and SLC1A5 independent of PTEN status, indicating that mechanistic target of rapamycin complex 1 (mTORC1) was needed for maximal AR-mediated glutamine uptake and PCa cell growth. Taken together, these data indicate that three well-established oncogenic drivers (AR, MYC and mTOR) function by converging to collectively increase the expression of glutamine transporters, thereby promoting glutamine uptake and subsequent prostate cancer cell growth. Implications: AR, MYC and mTOR converge to increase glutamine uptake and metabolism in prostate cancer through increasing the levels of glutamine transporters.

show abstract

Section: Discussionmentioning

confidence: 99%

Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer

White

Lin

Rajapakshe

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…1A). Based on these anilides, compounds with increased aromatic bulk were developed, which bind to ASCT2 with affinities in the low micromolar range [14]. …”

mentioning

confidence: 99%

“…The newly-identified biphenylmethyl derivative interacts with rat ASCT2 with a low micromolar apparent affinity. To our knowledge only one compound has been reported with higher affinity (1.3 μM, [14]), based on a substituted diaminobutanoic acid. However, this compound has substantially higher molecular weight, as well as hydrophobicity.…”

mentioning

confidence: 99%

Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

Singh

Tanui

Gameiro

et al. 2017

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.

show abstract

“…Collectively, our data suggests EWS cells preferentially utilize exogenous glutamine as a nutrient source and that this may be one of the mechanisms EWS cells use to survive in a nutrient‐poor environment. Inhibitors of SLC1A5/ASCT2 are under development for potential clinical application . Our data suggest that as the next generation of these inhibitors become available, they should be assessed in EWS model systems.…”

Section: Discussionmentioning

confidence: 95%

EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

Sen

Cross

Lorenzi

et al. 2018

Molecular Carcinogenesis

View full text Add to dashboard Cite

Ewing sarcoma (EWS) is a soft tissue and bone tumor that occurs primarily in adolescents and young adults. In most cases of EWS, the chimeric transcription factor, EWS‐FLI1 is the primary oncogenic driver. The epigenome of EWS cells reflects EWS‐FLI1 binding and activation or repression of transcription. Here, we demonstrate that EWS‐FLI1 positively regulates the expression of proteins required for serine‐glycine biosynthesis and uptake of the alternative nutrient source glutamine. Specifically, we show that EWS‐FLI1 activates expression of PHGDH, PSAT1, PSPH, and SHMT2. Using cell‐based studies, we also establish that EWS cells are dependent on glutamine for cell survival and that EWS‐FLI1 positively regulates expression of the glutamine transporter, SLC1A5 and two enzymes involved in the one‐carbon cycle, MTHFD2 and MTHFD1L. Inhibition of serine‐glycine biosynthesis in EWS cells impacts their redox state leading to an accumulation of reactive oxygen species, DNA damage, and apoptosis. Importantly, analysis of EWS primary tumor transcriptome data confirmed that the aforementioned genes we identified as regulated by EWS‐FLI1 exhibit increased expression compared with normal tissues. Furthermore, retrospective analysis of an independent data set generated a significant stratification of the overall survival of EWS patients into low‐ and high‐risk groups based on the expression of PHGDH, PSAT1, PSPH, SHMT2, SLC1A5, MTHFD2, and MTHFD1L. In summary, our study demonstrates that EWS‐FLI1 reprograms the metabolism of EWS cells and that serine‐glycine metabolism or glutamine uptake are potential targetable vulnerabilities in this tumor type.

show abstract

2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport

Cited by 54 publications

References 13 publications

Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer

Glutamine Transporters Are Targets of Multiple Oncogenic Signaling Pathways in Prostate Cancer

Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

EWS‐FLI1 reprograms the metabolism of Ewing sarcoma cells via positive regulation of glutamine import and serine‐glycine biosynthesis

Contact Info

Product

Resources

About