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Identification of the first highly selective inhibitor of human lactate dehydrogenase B

التفاصيل البيبلوغرافية
العنوان: Identification of the first highly selective inhibitor of human lactate dehydrogenase B
المؤلفون: Sachio Shibata, Satoshi Sogabe, Masanori Miwa, Takuya Fujimoto, Nobuyuki Takakura, Akihiko Naotsuka, Shuji Kitamura, Tomohiro Kawamoto, Tomoyoshi Soga
المصدر: Scientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
بيانات النشر: Nature Portfolio, 2021.
سنة النشر: 2021
المجموعة: LCC:Medicine
LCC:Science
مصطلحات موضوعية: Medicine, Science
الوصف: Abstract Lactate dehydrogenase (LDH) catalyses the conversion of pyruvate to lactate and NADH to NAD+; it has two isoforms, LDHA and LDHB. LDHA is a promising target for cancer therapy, whereas LDHB is necessary for basal autophagy and cancer cell proliferation in oxidative and glycolytic cancer cells. To the best of our knowledge, selective inhibitors for LDHB have not yet been reported. Here, we developed a high-throughput mass spectrometry screening system using an LDHB enzyme assay by detecting NADH and NAD+. As a result, we identified a small-molecule LDHB selective inhibitor AXKO-0046, an indole derivative. This compound exhibited uncompetitive LDHB inhibition (EC50 = 42 nM). X-ray crystallography revealed that AXKO-0046 bound to the potential allosteric site away from the LDHB catalytic active site, suggesting that targeting the tetramerisation interface of the two dimers is critical for the enzymatic activity. AXKO-0046 and its derivatives can be used to validate LDHB-associated pathways in cancer metabolism.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2045-2322
Relation: https://doaj.org/toc/2045-2322
DOI: 10.1038/s41598-021-00820-7
URL الوصول: https://doaj.org/article/f9c30a90aae44dd1abe0ffa04ef29aac
رقم الأكسشن: edsdoj.f9c30a90aae44dd1abe0ffa04ef29aac
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20452322
DOI:10.1038/s41598-021-00820-7