Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels
Abstract Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening ef...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40536-y |
| _version_ | 1827709651958890496 |
|---|---|
| author | Rachel J. Roth Flach Eliza Bollinger Allan R. Reyes Brigitte Laforest Bethany L. Kormos Shenping Liu Matthew R. Reese Luis A. Martinez Alsina Leanne Buzon Yuan Zhang Bruce Bechle Amy Rosado Parag V. Sahasrabudhe John Knafels Samit K. Bhattacharya Kiyoyuki Omoto John C. Stansfield Liam D. Hurley LouJin Song Lina Luo Susanne B. Breitkopf Mara Monetti Teresa Cunio Brendan Tierney Frank J. Geoly Jake Delmore C. Parker Siddall Liang Xue Ka N. Yip Amit S. Kalgutkar Russell A. Miller Bei B. Zhang Kevin J. Filipski |
| author_facet | Rachel J. Roth Flach Eliza Bollinger Allan R. Reyes Brigitte Laforest Bethany L. Kormos Shenping Liu Matthew R. Reese Luis A. Martinez Alsina Leanne Buzon Yuan Zhang Bruce Bechle Amy Rosado Parag V. Sahasrabudhe John Knafels Samit K. Bhattacharya Kiyoyuki Omoto John C. Stansfield Liam D. Hurley LouJin Song Lina Luo Susanne B. Breitkopf Mara Monetti Teresa Cunio Brendan Tierney Frank J. Geoly Jake Delmore C. Parker Siddall Liang Xue Ka N. Yip Amit S. Kalgutkar Russell A. Miller Bei B. Zhang Kevin J. Filipski |
| author_sort | Rachel J. Roth Flach |
| collection | DOAJ |
| description | Abstract Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor. |
| first_indexed | 2024-03-10T17:24:55Z |
| format | Article |
| id | doaj.art-f9d9823491ce46a3808353f3a122b4ab |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:24:55Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-f9d9823491ce46a3808353f3a122b4ab2023-11-20T10:13:45ZengNature PortfolioNature Communications2041-17232023-08-0114111410.1038/s41467-023-40536-ySmall molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levelsRachel J. Roth Flach0Eliza Bollinger1Allan R. Reyes2Brigitte Laforest3Bethany L. Kormos4Shenping Liu5Matthew R. Reese6Luis A. Martinez Alsina7Leanne Buzon8Yuan Zhang9Bruce Bechle10Amy Rosado11Parag V. Sahasrabudhe12John Knafels13Samit K. Bhattacharya14Kiyoyuki Omoto15John C. Stansfield16Liam D. Hurley17LouJin Song18Lina Luo19Susanne B. Breitkopf20Mara Monetti21Teresa Cunio22Brendan Tierney23Frank J. Geoly24Jake Delmore25C. Parker Siddall26Liang Xue27Ka N. Yip28Amit S. Kalgutkar29Russell A. Miller30Bei B. Zhang31Kevin J. Filipski32Pfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalPfizer Worldwide Research, Development & MedicalAbstract Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice. Structure-activity relationship studies led to identification of a thiazole series of BDK inhibitors; however, these inhibitors did not improve metabolism in mice upon chronic administration. While the thiophenes demonstrated sustained branched chain ketoacid (BCKA) lowering and reduced BDK protein levels, the thiazoles increased BCKAs and BDK protein levels. Thiazoles increased BDK proximity to BCKDH-E2, whereas thiophenes reduced BDK proximity to BCKDH-E2, which may promote BDK degradation. Thus, we describe two BDK inhibitor series that possess differing attributes regarding BDK degradation or stabilization and provide a mechanistic understanding of the desirable features of an effective BDK inhibitor.https://doi.org/10.1038/s41467-023-40536-y |
| spellingShingle | Rachel J. Roth Flach Eliza Bollinger Allan R. Reyes Brigitte Laforest Bethany L. Kormos Shenping Liu Matthew R. Reese Luis A. Martinez Alsina Leanne Buzon Yuan Zhang Bruce Bechle Amy Rosado Parag V. Sahasrabudhe John Knafels Samit K. Bhattacharya Kiyoyuki Omoto John C. Stansfield Liam D. Hurley LouJin Song Lina Luo Susanne B. Breitkopf Mara Monetti Teresa Cunio Brendan Tierney Frank J. Geoly Jake Delmore C. Parker Siddall Liang Xue Ka N. Yip Amit S. Kalgutkar Russell A. Miller Bei B. Zhang Kevin J. Filipski Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels Nature Communications |
| title | Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels |
| title_full | Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels |
| title_fullStr | Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels |
| title_full_unstemmed | Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels |
| title_short | Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels |
| title_sort | small molecule branched chain ketoacid dehydrogenase kinase bdk inhibitors with opposing effects on bdk protein levels |
| url | https://doi.org/10.1038/s41467-023-40536-y |
| work_keys_str_mv | AT racheljrothflach smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT elizabollinger smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT allanrreyes smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT brigittelaforest smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT bethanylkormos smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT shenpingliu smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT matthewrreese smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT luisamartinezalsina smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT leannebuzon smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT yuanzhang smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT brucebechle smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT amyrosado smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT paragvsahasrabudhe smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT johnknafels smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT samitkbhattacharya smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT kiyoyukiomoto smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT johncstansfield smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT liamdhurley smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT loujinsong smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT linaluo smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT susannebbreitkopf smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT maramonetti smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT teresacunio smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT brendantierney smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT frankjgeoly smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT jakedelmore smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT cparkersiddall smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT liangxue smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT kanyip smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT amitskalgutkar smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT russellamiller smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT beibzhang smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels AT kevinjfilipski smallmoleculebranchedchainketoaciddehydrogenasekinasebdkinhibitorswithopposingeffectsonbdkproteinlevels |