NCT-501 is a potent and selective theophylline-based inhibitor of aldehydedehydrogenase 1A1 (ALDH1A1), inhibits hALDH1A1 with IC50 of 40 nM, typically shows better selectivity over other ALDH isozymes and other dehydrogenases (hALDH1B1, hALDH3A1, and hALDH2, IC50 > 57 μM).
The human genome encodes 19 aldehyde dehydrogenase (ALDH) enzymes that metabolize reactive aldehydes to their corresponding carboxylic acid derivatives. Unbalanced biological activity of ALDHs and specific contribution to their metabolism pathway have been associated in a variety of disease states, including alcoholic liver disease, type 2 hyperprolinemia, hyperammonemia, Parkinson’s disease, and cancers [3]. NCT-501 is a potent and selective theophylline-based inhibitor of aldehyde dehydrogenase 1A1 (ALDH1A1), inhibits hALDH1A1 with IC50 of 40 nM, typically shows better selectivity over other ALDH isozymes and other dehydrogenases (hALDH1B1, hALDH3A1, and hALDH2, IC50 >57 μM) [3]. In vitro, NCT-501 shows a 16% decrease in the Cal-27 CisR cell line at 20 nM concentration, though the difference was not statistically significant [4]. The permeability measured in Caco-2 cell line indicates that NCT-501 exhibits excellent permeability and does not seem to be a substrate of transporters, such as P-gp [3]. Reasonable volume of distribution (Vss = 1.8 L/kg) but short half-life (t1/2 < 1 h) and high clearance level (CL = 98 mL min−1 kg−1) indicate that 64 is well absorbed and distributed but rapidly metabolized and/or excreted. This is consistent with the finding of short t1/2 of CD1 mouse liver microsomal stability (17 min, multipoint format) [3]. NCT-501 (100 µg/animal; i.t.; every alternate day for 20 days) shows a 78% inhibition in tumor growth in Cal-27 CisR derived xenografts [5].
作用机制
NCT-501 is substrate noncompetitive inhibitor, which bind near the solvent exposed exit of substrate-binding site [3].
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