Design and Synthesis of Novel Lactate Dehydrogenase A Inhibitors by Fragment-Based Lead Generation

Abstract

Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate, utilizing NADH as a cofactor. It has been identified as a potential therapeutic target in the area of cancer metabolism. In this manuscript we report our progress using fragment-based lead generation (FBLG), assisted by X-ray crystallography to develop small molecule LDHA inhibitors. Fragment hits were identified through NMR and SPR screening and optimized into lead compounds with nanomolar binding affinities via fragment linking. Also reported is their modification into cellular active compounds suitable for target validation work.

Lactate dehydrogenase 5: An old friend and a new hope in the war on cancer

“…At present, every month brings new information on novel LDH-5 inhibitors that are being actively identified, designed and synthesized [92][93][94]. Therefore, it can be expected that anti-LDH-5 drugs will soon be successfully developed for clinical use.…”

Synthesis and biological evaluation of N-hydroxybenzimidazoles as potential anticancer agents targeting human lactate dehydrogenase A

“…over-expressed in human tumor tissues [15]. In addition, small hairpin RNA-meditated knock-down of LDHA in tumor cells induced a decrease in cell proliferation [16][17][18]. These observations indicate that LDHA can be an attractive target for inhibiting tumor proliferation [19][20][21][22].…”

An update on therapeutic opportunities offered by cancer glycolytic metabolism

“…This inhibitor showed an IC 50 value of 0.27 lM and a K d value of 0.008 lM in the BIAcore binding affinity assay but lacked of any cellular activity, probably because of the diacid functionality that hinders membrane permeability. 55 Screening of the Genentech/Roche corporate compound collection and lead optimization efforts produced two potent LDH-A inhibitors: compound 30 possessing a 2-thio-6-oxo-1,6-dihydropyrimidine structure and the 2-amino-5-aryl-pyrazine 31 (Fig. 7).…”

“…61 Recent studies of the chemical class of N-hydroxyindole-based LDH-A-inhibitors produced several compounds that inhibit LDH-A in the low micromolar range. [62][63][64][65][66] It should be mentioned that results from surface plasmon resonance experiments carried out by Astra Zeneca on one of these compounds 55 were ambiguous and led the authors to hypothesize the occurrence of significant levels of nonspecific binding. Nevertheless, a recent study employing an external cavity laser (ECL) biosensor seems to indicate that this type of inhibitors display a specific binding to LDH-A.…”