Browsing by Author "Huddle, Brandt C."

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    Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of Aldehyde Dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy
    (Elsevier, 2021-02) Huddle, Brandt C.; Grimley, Edward; Chtcherbinine, Mikhail; Buchman, Cameron D.; Takahashi, Cyrus; Debnath, Bikash; McGonigal, Stacy C.; Mao, Shuai; Li, Siwei; Felton, Jeremy; Pan, Shu; Wen, Bo; Sun, Duxin; Neamati, Nouri; Buckanovich, Ronald J.; Hurley, Thomas D.; Larsen, Scott D.; Biochemistry and Molecular Biology, School of Medicine
    There is strong evidence that inhibition of one or more Aldehyde Dehydrogenase 1A (ALDH1A) isoforms may be beneficial in chemotherapy-resistant ovarian cancer and other tumor types. While many previous efforts have focused on development of ALDH1A1 selective inhibitors, the most deadly ovarian cancer subtype, high-grade serous (HGSOC), exhibits elevated expression of ALDH1A3. Herein, we report continued development of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in this critical tumor subtype. Optimization of the CM39 scaffold, aided by metabolite ID and several new ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular ALDH inhibition in HGSOC cell lines, and substantial improvements in microsomal stability culminating in orally bioavailable compounds. We demonstrate that two compounds 68 and 69 are able to synergize with chemotherapy in a resistant cell line and patient-derived HGSOC tumor spheroids, indicating their suitability for future in vivo proof of concept experiments.
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    Development of substituted benzimidazoles as inhibitors of Human Aldehyde Dehydrogenase 1A Isoenzymes
    (Elsevier, 2024) Takahashi, Cyrus; Chtcherbinine, Mikhail; Huddle, Brandt C.; Wilson, Michael W.; Emmel, Timothy; Hohlman, Robert M.; McGonigal, Stacy; Buckanovich, Ronald J.; Larsen, Scott D.; Hurley, Thomas D.; Biochemistry and Molecular Biology, School of Medicine
    Aldehyde dehydrogenase 1A (ALDH1A) isoforms may be a useful target for overcoming chemotherapy resistance in high-grade serous ovarian cancer (HGSOC) and other solid tumor cancers. However, as different cancers express different ALDH1A isoforms, isoform selective inhibitors may have a limited therapeutic scope. Furthermore, resistance to an ALDH1A isoform selective inhibitor could arise via induction of expression of other ALDH1A isoforms. As such, we have focused on the development of pan-ALDH1A inhibitors, rather than on ALDH1A isoform selective compounds. Herein, we report the development of a new group of pan-ALDH1A inhibitors to assess whether broad spectrum ALDH1A inhibition is an effective adjunct to chemotherapy in HGSOC. Optimization of the CM10 scaffold, aided by ALDH1A1 crystal structures, led to improved biochemical potencies, improved cellular efficacy as demonstrated by reduction in ALDEFLUOR signal in HGSOC cells, and substantial improvements in liver microsomal stability. Based on this work we identified two compounds 17 and 25 suitable for future in vivo proof of concept experiments.
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    Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy
    (American Chemical Society, 2018-10-11) 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.; Biochemistry and Molecular Biology, School of Medicine
    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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    Structure-Based Optimization of a Novel Class of Aldehyde Dehydrogenase 1A (ALDH1A) Subfamily-Selective Inhibitors as Potential Adjuncts to Ovarian Cancer Chemotherapy
    (ACS, 2018-09) 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.; Biochemistry and Molecular Biology, School of Medicine
    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.