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

Brandt C. Huddle, Edward Grimley, Cameron D. Buchman, Mikhail Chtcherbinine, Bikash Debnath, Pooja Mehta, Kun Yang, Cynthia A. Morgan, Siwei Li, Jeremy Felton, Duxin Sun, Geeta Mehta, Nouri Neamati, Ronald J. Buckanovich, Thomas Hurley, Scott D. Larsen

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)8754-8773
Number of pages20
JournalJournal of Medicinal Chemistry
Volume61
Issue number19
DOIs
StatePublished - Oct 11 2018

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Aldehyde Dehydrogenase
Ovarian Neoplasms
Neoplastic Stem Cells
Protein Isoforms
Drug Therapy
Cisplatin
Cell Line
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy. / Huddle, Brandt C.; Grimley, Edward; Buchman, Cameron D.; Chtcherbinine, Mikhail; Debnath, Bikash; Mehta, Pooja; Yang, Kun; Morgan, Cynthia A.; Li, Siwei; Felton, Jeremy; Sun, Duxin; Mehta, Geeta; Neamati, Nouri; Buckanovich, Ronald J.; Hurley, Thomas; Larsen, Scott D.

In: Journal of Medicinal Chemistry, Vol. 61, No. 19, 11.10.2018, p. 8754-8773.

Research output: Contribution to journalArticle

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, T & Larsen, SD 2018, 'Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy', Journal of Medicinal Chemistry, vol. 61, no. 19, pp. 8754-8773. https://doi.org/10.1021/acs.jmedchem.8b00930
Huddle, Brandt C. ; Grimley, Edward ; Buchman, Cameron D. ; Chtcherbinine, Mikhail ; Debnath, Bikash ; Mehta, Pooja ; Yang, Kun ; Morgan, Cynthia A. ; Li, Siwei ; Felton, Jeremy ; Sun, Duxin ; Mehta, Geeta ; Neamati, Nouri ; Buckanovich, Ronald J. ; Hurley, Thomas ; Larsen, Scott D. / Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 19. pp. 8754-8773.
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