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

Abstract

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.

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells

“…Dimethyl ampal thiolester (DIMATE), an ALDH1 and ALDH3 inhibitor, depletes leukemia stem cells but, importantly, does not affect hematopoietic stem cells (Venton et al, 2016). More recently a potent ALDH1A1 selective inhibitor and a pan-ALDH1A inhibitor were found to synergize with chemotherapy (Huddle et al, 2018;Yang et al, 2018), whereas an ALDH-targeted pro-drug effectively eliminated ALDH bright melanoma cells (Sarvi et al, 2018).…”

Targeting Aldehyde Dehydrogenases to Eliminate Cancer Stem Cells in Gynecologic Malignancies

“…Medicinal chemistry optimization also led to the discovery of newly designed ALDH1A1 selective inhibitors NCT-505 and NCT-506 [138] (Table 2). These analogs showed target engagement in a cellular thermal shift assay (CETSA) in vitro.…”

Navigating the Synthesis of Quinoline Hybrid Molecules as Promising Anticancer Agents

“…This exciting result will give motivation to pharmacists for further anticancer drug detection (Scheme 16). [73] A scenario for the synthesis of quinoline-4-piperazine fused urea/thiourea derivatives was brought to the limelight of the literature by Viswas Raja Solomon and Sheetal Pundir et al with a scare variation in the active pharmacophore from sulfonyl to urea/thiourea. Nucleophilic substitution reaction of 4-chloroquinoline 83 with piperazine and RNCO/RNCS afforded the desired molecular hybrids 86 and 87.…”