ArticleEuropean journal of medicinal chemistry2021
Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy.
Article in European journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- A scaffold repositioning approach: dihydroBenzoImidazoTriazineDione (BITD) derivatives as selective ALDH1A1 inhibitors.Molecular diversity · 2026Article
- Integrated Approach of Machine Learning and High-Throughput Screening to Identify Chemical Probe Candidates Targeting Aldehyde Dehydrogenases.ACS pharmacology & translational science · 2025Article
- Development of substituted benzimidazoles as inhibitors of human aldehyde dehydrogenase 1A isoenzymes.Chemico-biological interactions · 2024Article
- Applications of oxetanes in drug discovery and medicinal chemistry.European journal of medicinal chemistry · 2023Review
- Oxetanes in Drug Discovery Campaigns.Journal of medicinal chemistry · 2023Review
- Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA-Approved List through Molecular Docking and Dynamic Simulation.BioMed research international · 2023Article
- A specific inhibitor of ALDH1A3 regulates retinoic acid biosynthesis in glioma stem cells.Communications biology · 2021Article
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Authors and funding
17 authors.
Funding
Abstract
There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds. We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments.
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