Aldehyde dehydrogenase enzymes (ALDHs) have a broad spectrum of biological activities through the oxidation of both endogenous and exogenous aldehydes. Unbalanced biological activity of ALDHs has been associated with a variety of disease states such as alcoholic liver disease, Parkinson’s disease, obesity, and Cancer. Increased expression of ALDH1A1 has been identified in a wide-range of human cancer stem cells and is associated with cancer relapse and poor prognosis, raising the potential of ALDH1A1 as a therapeutic target.

We performed a systematic medicinal chemistry optimization and biological characterization of newly designed quinoline series that ultimately led to potent ALDH1A1 inhibitors with excellent enzymatic potency and cellular activity (e.g. MIA PaCa-2, OV-90, HT-20 cancer cell lines), as well as improved eADME properties. This chemotype demonstrated a high degree of selectivity over other ALDH isozymes (ALDH1B1, ALDH3A1, and ALDH2) and other dehydrogenases (HPGD and HSD17ß4).

Further development of the series indicated that NCT-505 and NCT-506 exhibit low nanomolar potency in both enzymatic and cellular assays, demonstrate target engagement in a cellular thermal shift assay (CETSA) and are capable to inhibit the formation of 3D spheroid cultures of OV-90 ovarian cancer cells. In addition, lead compounds potentiated the cytotoxicity of Paclitaxel in SKOV-3-TR, a Taxol-resistant ovarian cancer cell line, which suggest the potential feasibility of combined treatment with existing cancer drugs. PK studies demonstrated that NCT-505 and NCT-506 have reasonable drug exposure via PO administration and should be suitable for in vivo proof of concept animal studies or other disease-relevant models and can be used for a better understanding of the physiological and pathophysiological actions of this enzyme.