Identification of small molecules targeting the tetrameric interface of lactate dehydrogenases for enhanced therapeutic strategies
(2024)
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- Abstract
- Lactate dehydrogenases (LDHs) are metabolic enzymes that sustain several pathogenic functions of cancer cells, making them promising anticancer targets. Traditional strategies targeting their catalytic site have been inconclusive. Given that LDHs function as tetramers, we focused on targeting their oligomeric interface. In this work, we aim to identify small molecule inhibitors for this purpose. We created and validated an innovative biophysical screening cascade using orthogonal biophysical methods, enzymatic assays, co-crystallographic studies and cellular engagement assays. This approach led to the identification of compounds that bind to the LDH oligomeric interface, interfere with tetramer formation and impacting enzyme activity. These findings offer a novel strategy for anticancer therapy by targeting a previously unexplored site on LDHs. This constitutes a promising avenue for the de novo design of LDH inhibitors, overcoming current challenges in effectively targeting these enzymes.
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Citations
Brustenga, C. (2024). Identification of small molecules targeting the tetrameric interface of lactate dehydrogenases for enhanced therapeutic strategies.