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

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

  • J Med Chem. 2018 Oct 11;61(19):8754-8773. doi: 10.1021/acs.jmedchem.8b00930.
Brandt C Huddle,  Edward Grimley,  Cameron D Buchman 1,  Mikhail Chtcherbinine 1,  Bikash Debnath,  Pooja Mehta 2,  Kun Yang 3,  Cynthia A Morgan 1,  Siwei Li 4,  Jeremy Felton 4,  Duxin Sun 4,  Geeta Mehta 2 5 6,  Nouri Neamati,  Ronald J Buckanovich 3,  Thomas D Hurley 1,  Scott D Larsen
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology , Indiana University School of Medicine , Indianapolis , Indiana 46202 , United States.
  • 2 Department of Materials Science Engineering , University of Michigan , Ann Arbor , Michigan 48109 , United States.
  • 3 Division of Hematology Oncology, Department of Internal Medicine , University of Michigan , Ann Arbor , Michigan 48109 , United States.
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy ; University of Michigan , Ann Arbor , Michigan 48109 , United States.
  • 5 Department of Biomedical Engineering , University of Michigan , Ann Arbor , Michigan 48109 , United States.
  • 6 Macromolecular Science and Engineering , University of Michigan , Ann Arbor , Michigan 48109 , United States.
PMID: 30221940 DOI: 10.1021/acs.jmedchem.8b00930
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.

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