Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19)

Desai, Jigar; Patel, Bhaumin; Darji, Brijesh; Gite, Archana; Panchal, Nandini; Bhosale, Gokul; Shedage, Sandeep A.; Patel, Sandip; Kadam, Pravin; Patel, Gautam; Srivastava, B.; Joharapurkar, Amit; Kshirsagar, Samadhan; Giri, Poonam; Bhayani, Hitesh; Patel, Ankit; Ghoshdastidar, Krishnarup; Bandyopadhyay, Debdutta; Kumar, Sanjay; Jain, Mukul; Sharma, R. P.

doi:10.1016/j.bmcl.2021.128421

Cited by 9 publications

(12 citation statements)

References 21 publications

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“…The key factor for the therapy seems to be the simultaneous inhibition of the epidermal growth factor receptor (EGFR), which may be activated as a result of BRAF inhibition. This leads to progressive tumor proliferation [ 98 ]. The previously obtained compounds [ 99 ] were modified in the C10 atom by extending the alkyl group in order to improve their binding affinity.…”

Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

Kozyra

Krasowska

Pitucha

2022

IJMS

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Malignant melanoma (MM) is the most lethal skin cancer. Despite a 4% reduction in mortality over the past few years, an increasing number of new diagnosed cases appear each year. Long-term therapy and the development of resistance to the drugs used drive the search for more and more new agents with anti-melanoma activity. This review focuses on the most recent synthesized anti-melanoma agents from 2020–2022. For selected agents, apart from the analysis of biological activity, the structure–activity relationship (SAR) is also discussed. To the best of our knowledge, the following literature review delivers the latest achievements in the field of new anti-melanoma agents.

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Section: The Most Potent Anti-melanoma Agent From Most Recent Studies...mentioning

confidence: 99%

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

Kozyra

Krasowska

Pitucha

2022

IJMS

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“…Desai et al obtained a novel 1,3-difluorophenoxy derivative with an inhibitory activity of neutral amino acid transporter B0AT1 [ 147 ]. B0AT1 is the major transporter of neutral apical amino acids [ 148 ].…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

“…In the diet induced obese (DIO) mice model, the proposed compound resulted in a significant improvement in insulin tolerance and a decrease in body weight. The most active compound bore 3,5-difluorophenoxy moiety [ 147 ].…”

Section: Novel Agent With the Terminal Phenoxy Group From The Most Re...mentioning

confidence: 99%

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Kozyra

Pitucha

2022

IJMS

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The terminal phenoxy group is a moiety of many drugs in use today. Numerous literature reports indicated its crucial importance for biological activity; thus, it is a privileged scaffold in medicinal chemistry. This review focuses on the latest achievements in the field of novel potential agents bearing a terminal phenoxy group in 2013–2022. The article provided information on neurological, anticancer, potential lymphoma agent, anti-HIV, antimicrobial, antiparasitic, analgesic, anti-diabetic as well as larvicidal, cholesterol esterase inhibitors, and antithrombotic or agonistic activities towards the adrenergic receptor. Additionally, for selected agents, the Structure–Activity–Relationship (SAR) is also discussed. Thus, this study may help the readers to better understand the nature of the phenoxy group, which will translate into rational drug design and the development of a more efficient drug. To the best of our knowledge, this is the first review devoted to an in-depth analysis of the various activities of compounds bearing terminal phenoxy moiety.

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“…Moreover, lack of B 0 AT1 has also been shown to improve glucose tolerance through a variety of mechanisms including elevated levels of FGF21, GLP-1 9 and reducing liver triglycerides 10 and may protect against kidney injury 11 . As a result, significant efforts are underway to develop high-affinity selective inhibitors of B 0 AT1 10,[12][13][14][15][16] . This has been accompanied by the development of variety of assays to measure B 0 AT1 activity, such as proteoliposomes 12 , solid supported membrane electrophysiology 16 , voltage-sensitive fluorescent dyes (FLIPR) 14,15 and classical radioactive flux assays 14,15 .…”

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confidence: 99%

“…Initially identified inhibitors of B 0 AT1 showed IC 50 values in the 10-100 µM range 12,14 , whereas inhibitors derived from high-throughput screening showed IC 50 -values in the range from 0.4-15 µM 10,15 . A medicinal chemistry approach subsequently improved the IC 50 of nimesulide analogues to compound 39 with an IC 50 of 0.035 µM 13 .…”

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confidence: 99%

Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)

Xu,

Hu,

Dai

et al. 2024

Preprint

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The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders. This discovery has resulted in a quest to identify high-affinity selective inhibitors of B0AT1 for the treatment of disorders of amino acid metabolism. Here we employed a medicinal chemistry approach to improve lead compounds that were identified in a previous high-throughput screen. This effort yielded a group of compounds that inhibited B0AT1 with IC50-values of 31-90 nM. High-resolution cryo-EM structures of B0AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a substantial movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

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Discovery of novel, potent and orally efficacious inhibitor of neutral amino acid transporter B0AT1 (SLC6A19)

Cited by 9 publications

References 21 publications

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

Terminal Phenoxy Group as a Privileged Moiety of the Drug Scaffold—A Short Review of Most Recent Studies 2013–2022

Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19)

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