Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity

Aldehyde
dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes
(exogenous and endogenous) and possess vital physiological and toxicological
functions in areas such as CNS, inflammation, metabolic disorders,
and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an
important biomarker in cancers and cancer stem cells (CSCs) indicating
the potential need for the identification and development of small
molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based
analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry
optimization and biological characterization led to the identification
of analogs with significantly improved enzymatic and cellular ALDH
inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular
thermal shift assay (CETSA), inhibited the formation of 3D spheroid
cultures of OV-90 cancer cells, and potentiated the cytotoxicity of
paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell
line. Lead compounds also exhibit high specificity over other ALDH
isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs
are also highlighted.