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Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

ABSTRACT: Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.

SUBMITTER: Christov PP

PROVIDER: S-EPMC8113097 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Optimization of ether and aniline based inhibitors of lactate dehydrogenase.

Christov Plamen P PP Kim Kwangho K Jana Somnath S Romaine Ian M IM Rai Ganesha G Mott Bryan T BT Allweil Alexander A AA Lamers Alexander A Brimacombe Kyle R KR Urban Daniel J DJ Lee Tobie D TD Hu Xin X Lukacs Christine M CM Davies Douglas R DR Jadhav Ajit A Hall Matthew D MD Green Neal N Moore William J WJ Stott Gordon M GM Flint Andrew J AJ Maloney David J DJ Sulikowski Gary A GA Waterson Alex G AG

Bioorganic & medicinal chemistry letters 20210324

Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. Thes ...[more]

PMID: 33771585

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