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.

中文翻译：

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NCT-501，一种基于茶碱的强效选择性醛脱氢酶1A1（ALDH1A1）抑制剂的发现

醛脱氢酶（ALDHs）代谢反应性醛，并在诸如CNS，代谢紊乱和癌症等领域具有重要的生理和毒理学功能。在许多恶性肿瘤和癌症干细胞中，增加的ALDH（例如ALDH1A1）基因表达和催化活性是至关重要的生物标志物，突出了对鉴定和开发小分子ALDH抑制剂的需求。描述了一系列新的基于茶碱的类似物作为有效的ALDH1A1抑制剂。通过定量高通量筛选（qHTS）活动确定的命中数的优化导致了具有增强的效价和早期ADME特性的类似物。这种化学型表现出对ALDH1A1的选择性高于ALDH3A1，ALDH1B1和ALDH2同工酶以及其他脱氢酶，例如HPGD和HSD17β4。而且，64（NCT-501）也被突出显示。