دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.
المؤلفون: Roth Flach RJ; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA. rachel.rothflach@pfizer.com., Bollinger E; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Reyes AR; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Laforest B; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Kormos BL; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Liu S; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Reese MR; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Martinez Alsina LA; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Buzon L; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Zhang Y; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Bechle B; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Rosado A; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Sahasrabudhe PV; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Knafels J; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Bhattacharya SK; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Omoto K; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Stansfield JC; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Hurley LD; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Song L; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Luo L; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Breitkopf SB; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Monetti M; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Cunio T; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Tierney B; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Geoly FJ; Pfizer Worldwide Research, Development & Medical, Groton, CT, 06340, USA., Delmore J; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Siddall CP; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Xue L; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Yip KN; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Kalgutkar AS; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Miller RA; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Zhang BB; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA., Filipski KJ; Pfizer Worldwide Research, Development & Medical, Cambridge, MA, 02139, USA. kevin.filipski@pfizer.com.
المصدر: Nature communications [Nat Commun] 2023 Aug 09; Vol. 14 (1), pp. 4812. Date of Electronic Publication: 2023 Aug 09.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Amino Acids, Branched-Chain*/metabolism , Thiophenes*/pharmacology, Mice ; Animals ; Phosphorylation ; Oxidoreductases/metabolism
مستخلص: 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.
(© 2023. Springer Nature Limited.)
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المشرفين على المادة: 0 (Amino Acids, Branched-Chain)
0 (Thiophenes)
EC 1.- (Oxidoreductases)
تواريخ الأحداث: Date Created: 20230809 Date Completed: 20230811 Latest Revision: 20231119
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10412597
DOI: 10.1038/s41467-023-40536-y
PMID: 37558654
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-40536-y