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

Abstract

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.

Cancer stem cell mediated acquired chemoresistance in head and neck cancer can be abrogated by aldehyde dehydrogenase 1 A1 inhibition

“…In vitro and in vivo studies in ovarian cancer have shown similar results wherein, siRNA-based ALDH1A1 targeting has sensitized the cells to Cisplatin/Taxol therapy and reduced tumor growth in xenograft models [44]. The use of the small molecule inhibitor, NCT-501, that specifically inhibits ALDH1A1 [27], provided similar results in this study. This molecule inhibited tumor burden in in vivo models and improved efficacy of Cisplatin in patient-derived ex vivo explant studies.…”

NFκB Promotes Ovarian Tumorigenesis via Classical Pathways That Support Proliferative Cancer Cells and Alternative Pathways That Support ALDH+ Cancer Stem–like Cells

“…ALDH enzyme activity is a common marker of cancer stem cells in a variety of tissues and is associated with high tumor-initiating capacity of ovarian cancer cells and poor outcomes for patients with ovarian cancer (32,47–49). Selective inhibitors of ALDH are in development and may provide a therapeutic benefit for tumor cells dependent on ALDH activity (42,48,50), particularly if used in combination with traditional chemotherapy. This study highlights how differential NF-κB signaling can maintain diverse phenotypes within the cancer spheroid.…”

Targeting Cancer Stem Cells with Small Molecules

“…NCT-501, which harbors a scaffold derived from caffeine, is a selective ALDH1 inhibitor. [66] It has been shown to be effective against patient-derived head and neck cancer cells, [67] where other conventional molecules were proven to be ineffective. The heterogeneous cell lines used in these studies had elevated levels of CD44, CD133 and ALDH1, indicating an increased CSC population in these tumors, which helps rationalize the susceptibility of these cells to NCT-501 treatment.…”