The Specific Monocarboxylate Transporter-1 (MCT-1) Inhibitor, AR-C117977, Induces Donor-Specific Suppression, Reducing Acute and Chronic Allograft Rejection in the Rat

Ekberg, Henrik; Qi, Zhongquan; Påhlman, Clara; Veress, B; Bundick, R. V.; Craggs, R.I.; Holness, Elain; Edwards, Susan; Murray, Clare; Ferguson, Douglas; Kerry, P.J.; Wilson, E. Lynette; Donald, David K.

doi:10.1097/01.tp.0000287541.53389.be

Cited by 32 publications

(23 citation statements)

References 21 publications

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“…A new class of specific and extremely high-affinity inhibitors of MCT1 have been discovered by AstraZeneca [35–37]. We have confirmed the ability of one of these inhibitors, AR-C155858, to inhibit MCT1 in rat erythrocytes with a K i value of approx.…”

Section: Introductionsupporting

confidence: 63%

The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein

Ovens

Manoharan

Wilson

et al. 2010

Biochemical Journal

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In mammalian cells, MCTs (monocarboxylate transporters) require association with an ancillary protein to enable plasma membrane expression of the active transporter. Basigin is the preferred binding partner for MCT1, MCT3 and MCT4, and embigin for MCT2. In rat and rabbit erythrocytes, MCT1 is associated with embigin and basigin respectively, but its sensitivity to inhibition by AR-C155858 was found to be identical. Using RT (reverse transcription)–PCR, we have shown that Xenopus laevis oocytes contain endogenous basigin, but not embigin. Co-expression of exogenous embigin was without effect on either the expression of MCT1 or its inhibition by AR-C155858. In contrast, expression of active MCT2 at the plasma membrane of oocytes was significantly enhanced by co-expression of exogenous embigin. This additional transport activity was insensitive to inhibition by AR-C155858 unlike that by MCT2 expressed with endogenous basigin that was potently inhibited by AR-C155858. Chimaeras and C-terminal truncations of MCT1 and MCT2 were also expressed in oocytes in the presence and absence of exogenous embigin. L-Lactate Km values for these constructs were determined and revealed that the TM (transmembrane) domains of an MCT, most probably TM7–TM12, but not the C-terminus, are the major determinants of L-lactate affinity, whereas the associated ancillary protein has little or no effect. Inhibitor titrations of lactate transport by these constructs indicated that embigin modulates MCT2 sensitivity to AR-C155858 through interactions with both the intracellular C-terminus and TMs 3 and 6 of MCT2. The C-terminus of MCT2 was found to be essential for its expression with endogenous basigin.

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Section: Introductionsupporting

confidence: 63%

The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein

Ovens

Manoharan

Wilson

et al. 2010

Biochemical Journal

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“…Interestingly, these extracellular α-syn aggregates can then transfer from neuron to neuron or from neuron to glial cell 105 where they can nucleate further intracellular aggregation and/or trigger neuro-inflammation and exacerbate the neurodegenerative process 69, 108 . Supporting the potential relevance of this process in the pathogenesis of α-synucleinopathies, previous studies have shown accumulation of α-syn in fetal grafted neurons in patients with PD 109, 110 , as well as in grafted neuronal precursor cells in the hippocampus 69 and basal ganglia 111 in mouse models. Interestingly, α-syn has also been shown to ectopically accumulate in oligodendroglial cells in multiple system atrophy (another synucleinopathy) 112 and in astroglial cells in PD 113, 114 .…”

Section: α-Synuclein and Diseasementioning

confidence: 72%

The many faces of α-synuclein: from structure and toxicity to therapeutic target

et al. 2012

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Disorders characterized by α-synuclein (α-syn) accumulation, Lewy body formation and parkinsonism (and in some cases dementia) are collectively known as Lewy body diseases. The molecular mechanism(s) through which α-syn abnormally accumulates and contributes to neurodegeneration in these disorders remains unknown. Here, we provide an overview of current knowledge and prevailing hypotheses regarding the conformational, oligomerization and aggregation states of α-syn and their role in regulating α-syn function in health and disease. Understanding the nature of the various α-syn structures, how they are formed, and their relative contributions to α-syn-mediated toxicity may inform future studies aiming to develop therapeutic prevention and intervention.

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“…Previously, a new class of specific and extremely potent inhibitors of MCT1 have been discovered by AstraZeneca that were reported to show no binding to MCT4 and exhibit lower-affinity binding to MCT2 [30–32]. The K d values for these inhibitors binding to endogenous MCT1 in rat and human cells was found to be in the low nanomolar region or less, as was also found for MCT1 expressed in Ins-1 cells that contain little or no endogenous MCT1 [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…However, this agent is at least two orders of magnitude more potent at inhibiting the mitochondrial pyruvate carrier than MCT1 [26–29]. Previously, a new class of specific and extremely high-affinity inhibitors of MCT1 have been discovered by AstraZeneca [30–32]. These compounds were originally identified as potent inhibitors of T-lymphocyte proliferation that act as immunosuppressants and were subsequently shown to bind to MCT1 and MCT2, but not MCT4 [30].…”

Section: Introductionmentioning

confidence: 99%

AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10

Ovens

Davies

Wilson

et al. 2010

Biochemical Journal

217

195

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In the present study we characterize the properties of the potent MCT1 (monocarboxylate transporter 1) inhibitor AR-C155858. Inhibitor titrations of L-lactate transport by MCT1 in rat erythrocytes were used to determine the Ki value and number of AR-C155858-binding sites (Et) on MCT1 and the turnover number of the transporter (kcat). Derived values were 2.3±1.4 nM, 1.29±0.09 nmol per ml of packed cells and 12.2±1.1 s−1 respectively. When expressed in Xenopus laevis oocytes, MCT1 and MCT2 were potently inhibited by AR-C155858, whereas MCT4 was not. Inhibition of MCT1 was shown to be time-dependent, and the compound was also active when microinjected, suggesting that AR-C155858 probably enters the cell before binding to an intracellular site on MCT1. Measurement of the inhibitor sensitivity of several chimaeric transporters combining different domains of MCT1 and MCT4 revealed that the binding site for AR-C155858 is contained within the C-terminal half of MCT1, and involves TM (transmembrane) domains 7–10. This is consistent with previous data identifying Phe360 (in TM10) and Asp302 plus Arg306 (TM8) as key residues in substrate binding and translocation by MCT1. Measurement of the Km values of the chimaeras for L-lactate and pyruvate demonstrate that both the C- and N-terminal halves of the molecule influence transport kinetics consistent with our proposed molecular model of MCT1 and its translocation mechanism that requires Lys38 in TM1 in addition to Asp302 and Arg306 in TM8 [Wilson, Meredith, Bunnun, Sessions and Halestrap (2009) J. Biol. Chem. 284, 20011–20021].

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The Specific Monocarboxylate Transporter-1 (MCT-1) Inhibitor, AR-C117977, Induces Donor-Specific Suppression, Reducing Acute and Chronic Allograft Rejection in the Rat

Abstract: This report describes a MCT-1 specific inhibitor having immunosuppressive activity on alloimmune responses and inducing donor-specific suppression.

Cited by 32 publications

References 21 publications

The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein

The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein

The many faces of α-synuclein: from structure and toxicity to therapeutic target

AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10

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