Open AccessProgress in the Field of Aldehyde Dehydrogenase Inhibitors: Novel Imidazo[1,2-a]pyridines against the 1A Family
Author(s) -
Luca Quattrini,
Edoardo Luigi Maria Gelardi,
Giovanni Petrarolo,
Giorgia Colombo,
Davide M. Ferraris,
Francesca Picarazzi,
Menico Rizzi,
Silvia Garavaglia,
Concettina La Motta
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00686
Subject(s) - aldehyde dehydrogenase , gene isoform , aldehyde , enzyme , isozyme , combinatorial chemistry , cancer , active site , in vitro , chemistry , dehydrogenase , biochemistry , cancer research , computational biology , stereochemistry , pharmacology , catalysis , biology , gene , genetics
Members of the aldehyde dehydrogenase 1A family are commonly acknowledged as hallmarks of cancer stem cells, and their overexpression is significantly associated with poor prognosis in different types of malignancies. Accordingly, treatments targeting these enzymes may represent a successful strategy to fight cancer. In this work we describe a novel series of imidazo[1,2- a ]pyridines, designed as aldehyde dehydrogenase inhibitors by means of a structure-based optimization of a previously developed lead. The novel compounds were evaluated in vitro for their activity and selectivity against the three isoforms of the ALDH1A family and investigated through crystallization and modeling studies for their ability to interact with the catalytic site of the 1A3 isoform. Compound 3f emerged as the first in class submicromolar competitive inhibitor of the target enzyme.