Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)

Aldehyde dehydrogenases (ALDHs) metabolize
reactive aldehydes and
possess important physiological and toxicological functions in areas
such as CNS, metabolic disorders, and cancers. Increased ALDH (e.g.,
ALDH1A1) gene expression and catalytic activity are vital biomarkers
in a number of malignancies and cancer stem cells, highlighting the
need for the identification and development of small molecule ALDH
inhibitors. A new series of theophylline-based analogs as potent ALDH1A1
inhibitors is described. The optimization of hits identified from
a quantitative high throughput screening (qHTS) campaign led to analogs
with improved potency and early ADME properties. This chemotype exhibits
highly selective inhibition against ALDH1A1 over ALDH3A1, ALDH1B1,
and ALDH2 isozymes as well as other dehydrogenases such as HPGD and
HSD17β4. Moreover, the pharmacokinetic evaluation of selected
analog 64 (NCT-501) is also highlighted.