2. Academic Validation
  3. Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)

Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1)

  • J Med Chem. 2015 Aug 13;58(15):5967-78. doi: 10.1021/acs.jmedchem.5b00577.
Shyh-Ming Yang 1,  Adam Yasgar 1,  Bettina Miller 2,  Madhu Lal-Nag 1,  Kyle Brimacombe 1,  Xin Hu 1,  Hongmao Sun 1,  Amy Wang 1,  Xin Xu 1,  Kimloan Nguyen 1,  Udo Oppermann 3 4,  Marc Ferrer 1,  Vasilis Vasiliou 2 5,  Anton Simeonov 1,  Ajit Jadhav 1,  David J Maloney 1
Affiliations

Affiliations

  • 1 †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • 2 ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
  • 3 §Botnar Research Center, NIHR Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K.
  • 4 ∥Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
  • 5 ⊥Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, Connecticut 06510, United States.
PMID: 26207746 DOI: 10.1021/acs.jmedchem.5b00577
Abstract

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.

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