title: Discovery of NCT-501, a Potent and Selective Theophylline-Based Inhibitor of Aldehyde Dehydrogenase 1A1 (ALDH1A1).
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.
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Shyh-Ming
authors.initials: SM
authors.lastname: Yang
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Adam
authors.initials: A
authors.lastname: Yasgar
authors.affiliation: ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.
authors.forename: Bettina
authors.initials: B
authors.lastname: Miller
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Madhu
authors.initials: M
authors.lastname: Lal-Nag
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Brimacombe
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Kimloan
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: §Botnar Research Center, NIHR Oxford Biomedical Research Unit, Oxford OX3 7LD, U.K.|∥Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Udo
authors.initials: U
authors.lastname: Oppermann
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: ‡Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States.|⊥Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, Connecticut 06510, United States.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: †National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000080924:Aldehyde Dehydrogenase 1 Family; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D050697:Retinal Dehydrogenase; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C000603359:NCT-501; D010879:Piperazines; D013806:Theophylline; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase