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.

乙醛脱氢酶（Aldehyde dehydrogenases, ALDHs）可介导外源性与内源性醛类的代谢，在中枢神经系统（Central Nervous System, CNS）、炎症反应、代谢紊乱以及癌症等领域发挥至关重要的生理与毒理学功能。部分ALDH亚型（如ALDH1A1）的过表达是癌症与癌症干细胞（Cancer Stem Cells, CSCs）的重要生物标志物，这提示亟需鉴定并开发小分子ALDH抑制剂。本文报道了一系列全新设计的喹啉类ALDH1A1抑制剂类似物。通过系统性药物化学优化与生物学表征，研究团队筛选得到了酶学与细胞水平ALDH抑制活性显著提升的类似物。所选类似物，例如86号化合物（NCT-505）与91号化合物（NCT-506），在细胞热转移实验（Cellular Thermal Shift Assay, CETSA）中证实了靶点结合能力，可抑制OV-90癌细胞的3D球体培养物形成，并在紫杉醇耐药卵巢癌细胞系SKOV-3-TR中增强紫杉醇的细胞毒性。先导化合物对其他ALDH同工酶及无关脱氢酶均表现出极高的特异性。此外，本文还重点阐述了所选类似物的体外ADME（吸收、分布、代谢、排泄，Absorption, Distribution, Metabolism, Excretion）谱与药代动力学评价结果。