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 D.; Larsen, Scott D.

doi:10.1021/acs.jmedchem.8b00930

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

Journal Article · Mon Sep 17 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00930· OSTI ID:1484792

Huddle, Brandt C. ^[1]; Grimley, Edward ^[2]; Buchman, Cameron D. ^[3]; Chtcherbinine, Mikhail ^[3]; Debnath, Bikash ^[1]; Mehta, Pooja ^[1]; Yang, Kun ^[1]; Morgan, Cynthia A. ^[3]; Li, Siwei ^[1]; Felton, Jeremy ^[1]; Sun, Duxin ^[1]; Mehta, Geeta ^[1]; Neamati, Nouri ^[1]; Buckanovich, Ronald J. ^[4]; Hurley, Thomas D. ^[3];

^[1]

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)
Indiana Univ. School of Medicine, Indianapolis, IN (United States)
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)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: 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

Grant/Contract Number:: AC02-06CH11357; W81XWH-13-1-0134

OSTI ID:: 1484792

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 19; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 37 works

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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

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