8T0N

Structure of Compound 4 bound to human ALDH1A1

8T0N の概要

• エントリーDOI: 10.2210/pdb8t0n/pdb
• 分子名称: Aldehyde dehydrogenase 1A1, YTTERBIUM (III) ION, 2-methoxy-6-{[(1-propyl-1H-benzimidazol-2-yl)amino]methyl}phenol, ... (6 entities in total)
• 機能のキーワード: inhibitor complex, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56253.93

構造登録者

Hurley, T.D. (登録日: 2023-06-01, 公開日: 2024-05-01)

主引用文献

Takahashi, C.,Chtcherbinine, M.,Huddle, B.C.,Wilson, M.W.,Emmel, T.,Hohlman, R.M.,McGonigal, S.,Buckanovich, R.J.,Larsen, S.D.,Hurley, T.D.
Development of substituted benzimidazoles as inhibitors of human aldehyde dehydrogenase 1A isoenzymes.
Chem.Biol.Interact., 391:110910-110910, 2024

PubMed Abstract: Aldehyde dehydrogenase 1A (ALDH1A) isoforms may be a useful target for overcoming chemotherapy resistance in high-grade serous ovarian cancer (HGSOC) and other solid tumor cancers. However, as different cancers express different ALDH1A isoforms, isoform selective inhibitors may have a limited therapeutic scope. Furthermore, resistance to an ALDH1A isoform selective inhibitor could arise via induction of expression of other ALDH1A isoforms. As such, we have focused on the development of pan-ALDH1A inhibitors, rather than on ALDH1A isoform selective compounds. Herein, we report the development of a new group of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in HGSOC. Optimization of the CM10 scaffold, aided by ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular efficacy as demonstrated by reduction in ALDEFLUOR signal in HGSOC cells, and substantial improvements in liver microsomal stability. Based on this work we identified two compounds 17 and 25 suitable for future in vivo proof of concept experiments.

PubMed: 38364885
DOI: 10.1016/j.cbi.2024.110910

実験手法

X-RAY DIFFRACTION (1.86 Å)