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Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels

Author

Listed:
  • Rachel J. Roth Flach

    (Pfizer Worldwide Research, Development & Medical)

  • Eliza Bollinger

    (Pfizer Worldwide Research, Development & Medical)

  • Allan R. Reyes

    (Pfizer Worldwide Research, Development & Medical)

  • Brigitte Laforest

    (Pfizer Worldwide Research, Development & Medical)

  • Bethany L. Kormos

    (Pfizer Worldwide Research, Development & Medical)

  • Shenping Liu

    (Pfizer Worldwide Research, Development & Medical)

  • Matthew R. Reese

    (Pfizer Worldwide Research, Development & Medical)

  • Luis A. Martinez Alsina

    (Pfizer Worldwide Research, Development & Medical)

  • Leanne Buzon

    (Pfizer Worldwide Research, Development & Medical)

  • Yuan Zhang

    (Pfizer Worldwide Research, Development & Medical)

  • Bruce Bechle

    (Pfizer Worldwide Research, Development & Medical)

  • Amy Rosado

    (Pfizer Worldwide Research, Development & Medical)

  • Parag V. Sahasrabudhe

    (Pfizer Worldwide Research, Development & Medical)

  • John Knafels

    (Pfizer Worldwide Research, Development & Medical)

  • Samit K. Bhattacharya

    (Pfizer Worldwide Research, Development & Medical)

  • Kiyoyuki Omoto

    (Pfizer Worldwide Research, Development & Medical)

  • John C. Stansfield

    (Pfizer Worldwide Research, Development & Medical)

  • Liam D. Hurley

    (Pfizer Worldwide Research, Development & Medical)

  • LouJin Song

    (Pfizer Worldwide Research, Development & Medical)

  • Lina Luo

    (Pfizer Worldwide Research, Development & Medical)

  • Susanne B. Breitkopf

    (Pfizer Worldwide Research, Development & Medical)

  • Mara Monetti

    (Pfizer Worldwide Research, Development & Medical)

  • Teresa Cunio

    (Pfizer Worldwide Research, Development & Medical)

  • Brendan Tierney

    (Pfizer Worldwide Research, Development & Medical)

  • Frank J. Geoly

    (Pfizer Worldwide Research, Development & Medical)

  • Jake Delmore

    (Pfizer Worldwide Research, Development & Medical)

  • C. Parker Siddall

    (Pfizer Worldwide Research, Development & Medical)

  • Liang Xue

    (Pfizer Worldwide Research, Development & Medical)

  • Ka N. Yip

    (Pfizer Worldwide Research, Development & Medical)

  • Amit S. Kalgutkar

    (Pfizer Worldwide Research, Development & Medical)

  • Russell A. Miller

    (Pfizer Worldwide Research, Development & Medical)

  • Bei B. Zhang

    (Pfizer Worldwide Research, Development & Medical)

  • Kevin J. Filipski

    (Pfizer Worldwide Research, Development & Medical)

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.

Suggested Citation

  • 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 &, 2023. "Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40536-y
    DOI: 10.1038/s41467-023-40536-y
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    References listed on IDEAS

    as
    1. Jacquelyn M. Walejko & Bridgette A. Christopher & Scott B. Crown & Guo-Fang Zhang & Adrian Pickar-Oliver & Takeshi Yoneshiro & Matthew W. Foster & Stephani Page & Stephan Vliet & Olga Ilkayeva & Micha, 2021. "Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Luca A Lotta & Robert A Scott & Stephen J Sharp & Stephen Burgess & Jian’an Luan & Therese Tillin & Amand F Schmidt & Fumiaki Imamura & Isobel D Stewart & John R B Perry & Luke Marney & Albert Koulman, 2016. "Genetic Predisposition to an Impaired Metabolism of the Branched-Chain Amino Acids and Risk of Type 2 Diabetes: A Mendelian Randomisation Analysis," PLOS Medicine, Public Library of Science, vol. 13(11), pages 1-22, November.
    3. Katherine A. Henzler-Wildman & Ming Lei & Vu Thai & S. Jordan Kerns & Martin Karplus & Dorothee Kern, 2007. "A hierarchy of timescales in protein dynamics is linked to enzyme catalysis," Nature, Nature, vol. 450(7171), pages 913-916, December.
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