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Progress in the Field of Aldehyde Dehydrogenase Inhibitors: Novel Imidazo[1,2‑a]pyridines against the 1A Family
journal contribution
posted on 2020-03-31, 15:33 authored by Luca Quattrini, Edoardo Luigi Maria Gelardi, Giovanni Petrarolo, Giorgia Colombo, Davide Maria Ferraris, Francesca Picarazzi, Menico Rizzi, Silvia Garavaglia, Concettina La MottaMembers 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.
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hallmarkfight cancernovel compoundssiteProgressaldehyde dehydrogenase inhibitors3 isoformmodeling studiescrystallizationaldehyde dehydrogenase 1strategyprognosisImidazotypeFamily Membersabilitystructure-based optimizationCompound 3 fALDH 1A familypyridineAldehyde Dehydrogenase Inhibitorsimidazoselectivityoverexpressionmalignancytarget enzymeclass submicromolarnovel series
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