Abstract:
:Aldehyde dehydrogenase (ALDH) activity is commonly used as a marker to identify cancer stem-like cells. The three ALDH1A isoforms have all been individually implicated in cancer stem-like cells and in chemoresistance; however, which isoform is preferentially expressed varies between cell lines. We sought to explore the structural determinants of ALDH1A isoform selectivity in a series of small-molecule inhibitors in support of research into the role of ALDH1A in cancer stem cells. An SAR campaign guided by a cocrystal structure of the HTS hit CM39 (7) with ALDH1A1 afforded first-in-class inhibitors of the ALDH1A subfamily with excellent selectivity over the homologous ALDH2 isoform. We also discovered the first reported modestly selective single isoform 1A2 and 1A3 inhibitors. Two compounds, 13g and 13h, depleted the CD133+ putative cancer stem cell pool, synergized with cisplatin, and achieved efficacious concentrations in vivo following IP administration. Compound 13h additionally synergized with cisplatin in a patient-derived ovarian cancer spheroid model.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Huddle BC,Grimley E,Buchman CD,Chtcherbinine M,Debnath B,Mehta P,Yang K,Morgan CA,Li S,Felton J,Sun D,Mehta G,Neamati N,Buckanovich RJ,Hurley TD,Larsen SDdoi
10.1021/acs.jmedchem.8b00930subject
Has Abstractpub_date
2018-10-11 00:00:00pages
8754-8773issue
19eissn
0022-2623issn
1520-4804journal_volume
61pub_type
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