NCT-501 is a potent and selective theophylline-based inhibitor of aldehyde dehydrogenase 1A1 (ALDH1A1).Aldehyde dehydrogenases (ALDHs) metabolize reactive aldehydes and play important physiological and toxicological functions in metabolic disorders and cancers. ALDH1A1can be used as the marker of malignant prostate stem cells and predictor of prostate cancer patients' outcome. Over-expression of ALDH is associated with some types of cancers. Selective inhibitors targeted ALDH isozymes could preventspheroids formation in vitro and the size of xenograft tumors formed in vivo.
For more than 450 human kinases, NCT-501 treatment at 10 µM inhibited ≥55% activity of these kinases. NCT-501 reversibly inhibited ALDH1A1.The plasma exposure for intraperitoneal administration (ip) at 30 mg/kg showed better than the oral administration (p.o) at 30 mg/kg. The values of AUC 24h were 5670 h·ng/mL and 484 h·ng/mL along with 100% and 29% bioavailability, respectively. The t1/2 was shorter than 1h. The clearance level was 98 mL/min/kg. These results together indicated that NCT-501 was well absorbed and distributed but rapidly metabolized or excreted. In vitro stability of NCT-501in CD1 mouse plasma was more than 60 min.
Reference:
[1].Yang S M, Yasgar A, Miller B, et al. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)[J]. Journal of medicinal chemistry, 2015, 58(15): 5967-5978.