Insight into the nucleoside transport and inhibition of human ENT1

Wu, Zhixiang; Han, Zhongjie; Zhou, Wenxue; Sun, Xiaohan; Cheng, Lei; Yang, Shuang; Hu, Jianping; Li, Chunhua

doi:10.1016/j.crstbi.2022.05.005

Cited by 2 publications

(2 citation statements)

References 78 publications

(92 reference statements)

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“…Other residues, such as Asparagine‐30, Methionine‐84, Phenylalanine‐334, and Asparagine‐338, are also important for the inhibitor sensitivity of ENT1 40–42 . Through molecular docking simulations, Aspartic acid‐341 and Arginine‐345 in ENT1 were found to be important in establishing interaction with the substrate, adenosine, but not with the inhibitor, dilazep 41 . Further molecular docking studies, along with pharmacophore modeling of ENT1 substrates or inhibitors, should provide insight into the selectivity of this transporter 32,33 .…”

Section: Structural and Functional Characteristics Of Ent1 And Ent2mentioning

confidence: 99%

“…[40][41][42] Through molecular docking simulations, Aspartic acid-341 and Arginine-345 in ENT1 were found to be important in establishing interaction with the substrate, adenosine, but not with the inhibitor, dilazep. 41 Further molecular docking studies, along with pharmacophore modeling of ENT1 substrates or inhibitors, should provide insight into the selectivity of this transporter. 32,33 While mutational analyses have been performed with human ENT2 to characterize its inhibitor sensitivity, a crystal structure for this transporter is still unavailable.…”

Section: Structural and Functional Characteristics Of Ent1 And Ent2mentioning

confidence: 99%

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Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Hau

Wright

Cherrington

2023

Clin Pharma and Therapeutics

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The US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) guidances on small‐molecule drug–drug interactions (DDIs), with input from the International Transporter Consortium (ITC), recommend the evaluation of nine drug transporters. Although other clinically relevant drug uptake and efflux transporters have been discussed in ITC white papers, they have been excluded from further recommendation by the ITC and are not included in current regulatory guidances. These include the ubiquitously expressed equilibrative nucleoside transporters (ENT) 1 and ENT2, which have been recognized by the ITC for their potential role in clinically relevant nucleoside analog drug interactions for patients with cancer. Although there is comparatively limited clinical evidence supporting their role in DDI risk or other adverse drug reactions (ADRs) compared with the nine highlighted transporters, several in vitro and in vivo studies have identified ENT interactions with non‐nucleoside/non‐nucleotide drugs, in addition to nucleoside/nucleotide analogs. Some noteworthy examples of compounds that interact with ENTs include cannabidiol and selected protein kinase inhibitors, as well as the nucleoside analogs remdesivir, EIDD‐1931, gemcitabine, and fialuridine. Consequently, DDIs involving the ENTs may be responsible for therapeutic inefficacy or off‐target toxicity. Evidence suggests that ENT1 and ENT2 should be considered as transporters potentially involved in clinically relevant DDIs and ADRs, thereby warranting further investigation and regulatory consideration.

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Section: Structural and Functional Characteristics Of Ent1 And Ent2mentioning

confidence: 99%

Section: Structural and Functional Characteristics Of Ent1 And Ent2mentioning

confidence: 99%

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Hau

Wright

Cherrington

2023

Clin Pharma and Therapeutics

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Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools

Dilweg,

Gorostiola González,

de Ruiter

et al. 2024

Purinergic Signalling

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The human equilibrative nucleoside transporter 1 (SLC29A1, hENT1) is a solute carrier that modulates the passive transport of nucleosides and nucleobases, such as adenosine. This nucleoside regulates various physiological processes, such as vasodilation and -constriction, neurotransmission and immune defense. Marketed drugs such as dilazep and dipyridamole have proven useful in cardiovascular afflictions, but the application of hENT1 inhibitors can be beneficial in a number of other diseases. In this study, 39 derivatives of dilazep’s close analogue ST7092 were designed, synthesized and subsequently assessed using [3H]NBTI displacement assays and molecular docking. Different substitution patterns of the trimethoxy benzoates of ST7092 reduced interactions within the binding pocket, resulting in diminished hENT1 affinity. Conversely, [3H]NBTI displacement by potentially covalent compounds 14b, 14c, and 14d resulted in high affinities (Ki values between 1.1 and 17.5 nM) for the transporter, primarily by the ability of accommodating the inhibitors in various ways in the binding pocket. However, any indication of covalent binding with amino acid residue C439 remained absent, conceivably as a result of decreased nucleophilic residue reactivity. In conclusion, this research introduces novel dilazep derivatives that are active as hENT1 inhibitors, along with the first high affinity dilazep derivatives equipped with an electrophilic warhead. These findings will aid the rational and structure-based development of novel hENT1 inhibitors and pharmacological tools to study hENT1's function, binding mechanisms, and its relevance in (patho)physiological conditions.

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Insight into the nucleoside transport and inhibition of human ENT1

Cited by 2 publications

References 78 publications

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Addressing the Clinical Importance of Equilibrative Nucleoside Transporters in Drug Discovery and Development

Exploring novel dilazep derivatives as hENT1 inhibitors and potentially covalent molecular tools

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