Browsing by Author "Buckanovich, Ronald J."

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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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    A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells
    (Elsevier, 2019-03-12) Chefetz, Ilana; Grimley, Edward; Yang, Kun; Hong, Linda; Vinogradova, Ekaterina V.; Suciu, Radu; Kovalenko, Ilya; Karnak, David; Morgan, Cynthia A.; Chtcherbinine, Mikhail; Buchman, Cameron; Huddle, Brandt; Barraza, Scott; Morgan, Meredith; Bernstein, Kara A.; Yoon, Euisik; Lombard, David B.; Bild, Andrea; Mehta, Geeta; Romero, Iris; Chiang, Chun-Yi; Landen, Charles; Cravatt, Benjamin; Hurley, Thomas D.; Larsen, Scott D.; Buckanovich, Ronald J.; Department of Biochemistry and Molecular Biology, School of Medicine
    Summary Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133+ ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.
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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.