Characterization of Two Distinct Structural Classes of Selective Aldehyde Dehydrogenase 1A1 Inhibitors

Abstract

Aldehyde dehydrogenases (ALDH) catalyze the irreversible oxidation of aldehydes to their corresponding carboxylic acid. Alterations in ALDH1A1 activity are associated with such diverse diseases as cancer, Parkinson’s disease, obesity, and cataracts. Inhibitors of ALDH1A1 could aid in illuminating the role of this enzyme in disease processes. However, there are no commercially available selective inhibitors for ALDH1A1. Here we characterize two distinct chemical classes of inhibitors that are selective for human ALDH1A1 compared to eight other ALDH isoenzymes. The prototypical members of each structural class, CM026 and CM037, exhibit sub-micromolar inhibition constants, but have different mechanisms of inhibition. The crystal structures of these compounds bound to ALDH1A1 demonstrate that they bind within the aldehyde binding pocket of ALDH1A1 and exploit the presence of a unique Glycine residue to achieve their selectivity. These two novel and selective ALDH1A1 inhibitors may serve as chemical tools to better understand the contributions of ALDH1A1 to normal biology and to disease states.

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

“…27 This structure along with kinetic studies indicated that these analogs are substrate noncompetitive inhibitors, which bind near the solvent exposed exit of substrate-binding site. Independent kinetic studies in our laboratory corroborated these findings (data not shown).…”

“…This is consistent with reported cocrystallized structure of a theophylline-based analog that R 1 substitution points toward the space surrounded by greasy residues Phe171 and Phe466. 27 …”

Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors

“…However, several crystal structures of ALDH1A1-inhibitor complexes have been reported recently. 21,27,28 Indole-2.3-dinones and diethylaminobenzaldehyde (DEAB) are pan-ALDH1A inhibitors reported to covalently attack the catalytic cysteines of ALDH3A1 and ALDH7A1. 29–31 Analogues of duocarmycin form covalent bonds with catalytic and noncatalytic cysteine residues in ALDH1A1.…”

Inhibition of the Aldehyde Dehydrogenase 1/2 Family by Psoralen and Coumarin Derivatives

“…Compounds have the ability to bind throughout the aromatic region in ALDH1A1 due to Gly458, as previously described for the ALDH1A1 inhibitors CM037 and CM026. 49 …”