title: Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase.
abstract: Aberrant cellular metabolism drives cancer proliferation and metastasis. ATP citrate lyase (ACL) plays a critical role in generating cytosolic acetyl CoA, a key building block for de novo fatty acid and cholesterol biosynthesis. ACL is overexpressed in cancer cells, and siRNA knockdown of ACL limits cancer cell proliferation and reduces cancer stemness. We characterized a new class of ACL inhibitors bearing the key structural feature of the natural product emodin. Structure-activity relationship (SAR) study led to the identification of 1d as a potent lead that demonstrated dose-dependent inhibition of proliferation and cancer stemness of the A549 lung cancer cell line. Computational modeling indicates this class of inhibitors occupies an allosteric binding site and blocks the entrance of the substrate citrate to its binding site.
authors.affiliation: Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steffi K
authors.initials: SK
authors.lastname: Koerner
authors.affiliation: Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Hanai
authors.affiliation: Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Bai
authors.affiliation: Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Finith E
authors.initials: FE
authors.lastname: Jernigan
authors.affiliation: Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Miwa
authors.initials: M
authors.lastname: Oki
authors.affiliation: Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Chieko
authors.initials: C
authors.lastname: Komaba
authors.affiliation: Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Emi
authors.initials: E
authors.lastname: Shuto
authors.affiliation: Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: vsukhatm@bidmc.harvard.edu.
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.affiliation: Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: lsun1@bidmc.harvard.edu.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004642:Emodin / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D014411:Neoplastic Stem Cells / Q000187:drug effects; D000072417:Protein Domains; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D001275:ATP Citrate (pro-S)-Lyase; D004642:Emodin
keywords: ATP citrate lyase inhibitor; Cancer stem cell; Emodin anthraquinones and anthracenone; Lipogenesis