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

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. In this work, 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.

Authors:
 [1];  [2];  [3];  [3];  [1];  [1];  [1];  [3];  [1];  [1];  [1];  [1];  [1];  [4];  [3]; ORCiD logo [1]
  1. Univ. of Michigan, Ann Arbor, MI (United States)
  2. Univ. of Pittsburgh Medical Center, Pittsburgh, PA (United States); Magee Womens Research Inst., Pittsburgh, PA (United States)
  3. Indiana Univ. School of Medicine, Indianapolis, IN (United States)
  4. Univ. of Michigan, Ann Arbor, MI (United States); Univ. of Pittsburgh Medical Center, Pittsburgh, PA (United States); Magee Womens Research Inst., Pittsburgh, PA (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); Center for the Discovery of New Medicines; Michigan Ovarian Cancer Alliance; Rivkin Center for Ovarian Cancer; USDOD
OSTI Identifier:
1484792
Grant/Contract Number:  
AC02-06CH11357; W81XWH-13-1-0134
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 19; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; Cancer; Substituents; Cells; Inhibitors; Selectivity

Citation Formats

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 D., and 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. United States: N. p., 2018. Web. doi: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 D., & 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. United States. doi: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 D., and Larsen, Scott D. Mon . "Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy". United States. doi:10.1021/acs.jmedchem.8b00930. https://www.osti.gov/servlets/purl/1484792.
@article{osti_1484792,
title = {Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy},
author = {Huddle, Brandt C. and Grimley, Edward and Buchman, Cameron D. and Chtcherbinine, Mikhail and Debnath, Bikash and Mehta, Pooja and Yang, Kun and Morgan, Cynthia A. and Li, Siwei and Felton, Jeremy and Sun, Duxin and Mehta, Geeta and Neamati, Nouri and Buckanovich, Ronald J. and Hurley, Thomas D. and Larsen, Scott D.},
abstractNote = {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. In this work, 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.},
doi = {10.1021/acs.jmedchem.8b00930},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 19,
volume = 61,
place = {United States},
year = {2018},
month = {9}
}

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Ovarian Cancer Stem Cells: Role in Metastasis and Opportunity for Therapeutic Targeting
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