Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels
Vascular smooth muscle ATP-sensitive potassium (KATP) channels play critical roles in modulating vascular tone and thus represent important drug targets for diverse cardiovascular pathologies. Despite extensive research efforts spanning several decades, the search for selective inhibitors that can d...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2024-12-01
|
| Series: | Channels |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19336950.2024.2398565 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850169065686958080 |
|---|---|
| author | Kangjun Li Vaishali Satpute Janve Jerod Denton |
| author_facet | Kangjun Li Vaishali Satpute Janve Jerod Denton |
| author_sort | Kangjun Li |
| collection | DOAJ |
| description | Vascular smooth muscle ATP-sensitive potassium (KATP) channels play critical roles in modulating vascular tone and thus represent important drug targets for diverse cardiovascular pathologies. Despite extensive research efforts spanning several decades, the search for selective inhibitors that can discriminate between vascular KATP (i.e. Kir6.1/SUR2B) and pancreatic and brain KATP (i.e. Kir6.2/SUR1) channels has, until recently, been unsuccessful. Our group therefore carried out a high-throughput screen of chemically diverse compounds with the goal of discovering specific Kir6.1/SUR2B inhibitors. This screen identified several novel classes of Kir6.1/SUR2B inhibitors, including the first potent (IC50 ~100 nM) and selective inhibitor published to date, termed VU0542270. Here, we expand on this work by disclosing the identity and pharmacological properties of four additional Kir6.1/SUR2B inhibitors that are structurally unrelated to Kir to VU0542270. These inhibitors, named VU0212387, VU0543336, VU0605768, and VU0544086, inhibit Kir6.1/SUR2B with IC50 values ranging from approximately 100 nM to 1 µM and exhibit no apparent inhibitory activity toward Kir6.2/SUR1. Functional analysis of heterologously expressed subunit combinations of Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B and demonstrated that all four inhibitors act on SUR2 to induce channel inhibition. Interestingly, VU0543336 and VU0212387 exhibit paradoxical stimulatory effects on Kir6.2/SUR1 at higher doses. This study broadens our understanding of KATP channel pharmacology, generally, and reveals novel chemical matter for the development of Kir6.1/SUR2-selective drugs, specifically. |
| format | Article |
| id | doaj-art-e5a4d005f8a84498b4a79a932f8b0c3d |
| institution | OA Journals |
| issn | 1933-6950 1933-6969 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Channels |
| spelling | doaj-art-e5a4d005f8a84498b4a79a932f8b0c3d2025-08-20T02:20:49ZengTaylor & Francis GroupChannels1933-69501933-69692024-12-0118110.1080/19336950.2024.2398565Characterization of four structurally diverse inhibitors of SUR2-containing KATP channelsKangjun Li0Vaishali Satpute Janve1Jerod Denton2Department of Pharmacology, Vanderbilt University, Nashville, TNDepartment of Anesthesiology, Vanderbilt University Medical Center, Nashville, TNDepartment of Pharmacology, Vanderbilt University, Nashville, TNVascular smooth muscle ATP-sensitive potassium (KATP) channels play critical roles in modulating vascular tone and thus represent important drug targets for diverse cardiovascular pathologies. Despite extensive research efforts spanning several decades, the search for selective inhibitors that can discriminate between vascular KATP (i.e. Kir6.1/SUR2B) and pancreatic and brain KATP (i.e. Kir6.2/SUR1) channels has, until recently, been unsuccessful. Our group therefore carried out a high-throughput screen of chemically diverse compounds with the goal of discovering specific Kir6.1/SUR2B inhibitors. This screen identified several novel classes of Kir6.1/SUR2B inhibitors, including the first potent (IC50 ~100 nM) and selective inhibitor published to date, termed VU0542270. Here, we expand on this work by disclosing the identity and pharmacological properties of four additional Kir6.1/SUR2B inhibitors that are structurally unrelated to Kir to VU0542270. These inhibitors, named VU0212387, VU0543336, VU0605768, and VU0544086, inhibit Kir6.1/SUR2B with IC50 values ranging from approximately 100 nM to 1 µM and exhibit no apparent inhibitory activity toward Kir6.2/SUR1. Functional analysis of heterologously expressed subunit combinations of Kir6.1, Kir6.2, SUR1, SUR2A, and SUR2B and demonstrated that all four inhibitors act on SUR2 to induce channel inhibition. Interestingly, VU0543336 and VU0212387 exhibit paradoxical stimulatory effects on Kir6.2/SUR1 at higher doses. This study broadens our understanding of KATP channel pharmacology, generally, and reveals novel chemical matter for the development of Kir6.1/SUR2-selective drugs, specifically.https://www.tandfonline.com/doi/10.1080/19336950.2024.2398565Potassium channelsKATP channelsSUR2Bdrug discoverychannelopathiescardiovascular disease |
| spellingShingle | Kangjun Li Vaishali Satpute Janve Jerod Denton Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels Channels Potassium channels KATP channels SUR2B drug discovery channelopathies cardiovascular disease |
| title | Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels |
| title_full | Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels |
| title_fullStr | Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels |
| title_full_unstemmed | Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels |
| title_short | Characterization of four structurally diverse inhibitors of SUR2-containing KATP channels |
| title_sort | characterization of four structurally diverse inhibitors of sur2 containing katp channels |
| topic | Potassium channels KATP channels SUR2B drug discovery channelopathies cardiovascular disease |
| url | https://www.tandfonline.com/doi/10.1080/19336950.2024.2398565 |
| work_keys_str_mv | AT kangjunli characterizationoffourstructurallydiverseinhibitorsofsur2containingkatpchannels AT vaishalisatputejanve characterizationoffourstructurallydiverseinhibitorsofsur2containingkatpchannels AT jeroddenton characterizationoffourstructurallydiverseinhibitorsofsur2containingkatpchannels |