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Imidazo[1,2-a]pyridine Derivatives as Aldehyde Dehydrogenase Inhibitors: Novel Chemotypes to Target Glioblastoma Stem Cells.

Abstract：

:Glioblastoma multiforme (GBM) is the deadliest form of brain tumor. It is known for its ability to escape the therapeutic options available to date thanks to the presence of a subset of cells endowed with stem-like properties and ability to resist to cytotoxic treatments. As the cytosolic enzyme aldehyde dehydrogenase 1A3 turns out to be overexpressed in these kinds of cells, playing a key role for their vitality, treatments targeting this enzyme may represent a successful strategy to fight GBM. In this work, we describe a novel class of imidazo[1,2-a]pyridine derivatives as aldehyde dehydrogenase 1A3 inhibitors, reporting the evidence of their significance as novel drug candidates for the treatment of GBM. Besides showing an interesting functional profile, in terms of activity against the target enzyme and selectivity toward highly homologous isoenzymes, representative examples of the series also showed a nanomolar to picomolar efficacy against patient-derived GBM stem-like cells, thus proving the concept that targeting aldehyde dehydrogenase might represent a novel and promising way to combat GBM by striking its ability to divide immortally.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Quattrini L,Gelardi ELM,Coviello V,Sartini S,Ferraris DM,Mori M,Nakano I,Garavaglia S,La Motta C

doi

10.1021/acs.jmedchem.9b01910

subject

Has Abstract

pub_date

2020-05-14 00:00:00

pages

4603-4616

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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