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Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors.

ABSTRACT: Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on ?-cyanocinnamic acid structural template. Candidate inhibitors 1-9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and OxPhos efficiently in MCT1 expressing colorectal adenocarcinoma WiDr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells. Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria. In vivo tumor growth inhibition studies in WiDr and MDA-MB-231 xenograft tumor models in mice indicate that the candidate compound 9 exhibits a significant single agent activity.

SUBMITTER: Jonnalagadda S

PROVIDER: S-EPMC6481325 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors.

Jonnalagadda Shirisha S Jonnalagadda Sravan K SK Ronayne Conor T CT Nelson Grady L GL Solano Lucas N LN Rumbley Jon J Holy Jon J Mereddy Venkatram R VR Drewes Lester R LR

Oncotarget 20190322 24

Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-cyanocinnamic acid structural template. Candidate inhibitors 1-9 have been evaluated for <i>in vitro</i> cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. <i>In vitro</i> effects on e ...[more]

PMID: 31040927

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Project description:The drug of abuse, γ-hydroxybutyric acid (GHB), is commonly co-ingested with ethanol, resulting in a high incidence of toxicity and death. Our laboratory has previously reported that GHB is a substrate for the monocarboxylate transporters (MCTs), necessary for its absorption, renal clearance, and tissue distribution, including across the blood-brain barrier. Our goal was to investigate the drug-drug interaction (DDI) between GHB and ethanol and to evaluate MCT1 inhibition as a strategy to reverse toxicity. The toxicokinetics of this DDI were investigated, including brain-to-plasma concentration ratios, in the presence and absence of ethanol. The toxicodynamic parameters examined were respiratory depression (breathing frequency, tidal volume) and sedation (time of return-of-righting reflex). Ethanol was administered (2 g/kg i.v.) 5 minutes before the intravenous or oral administration of GHB, and MCT1 inhibitors AZD-3965 and AR-C155858 (5 mg/kg i.v.) were administered 60 minutes after GHB administration. Ethanol administration did not alter the toxicokinetics or respiratory depression caused by GHB after intravenous or oral administration; however, it significantly increased the sedation effect, measured by return-to-righting time. AZD-3965 or AR-C155858 significantly decreased the effects of the co-administration of GHB and ethanol on respiratory depression and sedation of this DDI and decreased brain concentrations and the brain-to-plasma concentration ratio of GHB. The results indicate that ethanol co-administered with GHB increases toxicity and that MCT1 inhibition is effective in reversing toxicity by inhibiting GHB brain uptake when given after GHB-ethanol administration. SIGNIFICANCE STATEMENT: These studies investigated the enhanced toxicity observed clinically when γ-hydroxybutyric acid (GHB) is co-ingested with alcohol and evaluated strategies to reverse this toxicity. The effects of the novel monocarboxylate transporter 1 (MCT1) inhibitors AR-C155858 and AZD-3965 on this drug-drug interaction have not been studied before, and these preclinical studies indicate that MCT1 inhibitors can decrease brain concentrations of GHB by inhibiting brain uptake, even when administered at times after GHB-ethanol. AZD-3965 represents a potential treatment strategy for GHB-ethanol overdoses.

Project description:Monocarboxylate transporter 8 (MCT8) deficiency or the Allan-Herndon-Dudley Syndrome (AHDS) is an X-linked psychomotor disability syndrome with around 320 clinical cases described worldwide. SLC16A2 gene mutations, encoding the thyroid hormone (TH) transporter MCT8, result in intellectual disability due to impaired TH uptake in the developing brain. MCT8 deficiency is a multi-organ affecting disease with a predominant neuronal cell-based pathology, with the glial component inadequately investigated. However, deficiency in myelin, a key component of white matter (WM) enabling fast nerve conduction, is a TH-dependent hallmark of the disease. Nevertheless, analysis of the myelin status in AHDS patients has led to conflicting interpretations. The majority of individual case studies reported delayed myelination, that was restored later in life. In contrast, post-mortem studies and high-resolution MRIs detected WM (micro-) abnormalities throughout adolescence, suggesting permanent hypomyelination. Thus, interpretations vary depending on methodology to investigate WM microstructure. Further, it is unknown whether the mutation within the MCT8 is linked to the severity of the myelin deficiency. Consequently, terminology is inconsistent among reports, and AHDS is occasionally misdiagnosed as another WM disorder. The evolutionary conserved TH signaling pathway that promotes the generation of myelinating oligodendrocytes enabled deciphering how the lack of MCT8 might affect myelinogenesis. Linking patient findings on myelination to those obtained from models of MCT8 deficiency revealed underlying pathophysiological mechanisms, but knowledge gaps remain, notably how myelination progresses both spatially and temporally in MCT8 deficiency. This limits predicting how myelin integrity might benefit therapeutically, and when to initiate. A recurrent observation in clinical trials is the absence of neurological improvement. Testing MCT8-independent thyromimetics in models, and evaluating treatments used in other demyelinating diseases, despite different etiologies, is crucial to propose new therapeutic strategies combatting this devastating disease.

Dataset Information

Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors.

Publications

Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors.

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