Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy

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.