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Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A.


ABSTRACT: Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumors, thereby sustaining high glycolysis rates, tumor growth, and chemoresistance. High-throughput screening resulted in the identification of phthalimide and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors, selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization experiments confirmed target engagement in addition to demonstrating binding to a novel allosteric binding site present in all four LDHA subunits of the LDH5 homotetramer.

SUBMITTER: Friberg A 

PROVIDER: S-EPMC7288559 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Structural Evidence for Isoform-Selective Allosteric Inhibition of Lactate Dehydrogenase A.

Friberg Anders A   Rehwinkel Hartmut H   Nguyen Duy D   Pütter Vera V   Quanz Maria M   Weiske Jörg J   Eberspächer Uwe U   Heisler Iring I   Langer Gernot G  

ACS omega 20200527 22


Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumors, thereby sustaining high glycolysis rates, tumor growth, and chemoresistance. High-throughput screening resulted in the identification of phthalimide and dibenzofuran derivatives as novel lactate dehydrogenase inhibitors, selectively inhibiting the activity of the LDHA isoenzyme. Cocrystallization experiments confirmed target engagement in addition to demonstrating binding to a novel allosteric binding site present in all four  ...[more]

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