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Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase.
Koerner, Steffi K; Hanai, Jun-Ichi; Bai, Sha; Jernigan, Finith E; Oki, Miwa; Komaba, Chieko; Shuto, Emi; Sukhatme, Vikas P; Sun, Lijun.
Affiliation
  • Koerner SK; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Hanai JI; 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.
  • Bai S; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Jernigan FE; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Oki M; Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Komaba C; Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Shuto E; Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Sukhatme VP; 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; Hematolo
  • Sun L; 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.
Eur J Med Chem ; 126: 920-928, 2017 Jan 27.
Article in En | MEDLINE | ID: mdl-27997879
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: ATP Citrate (pro-S)-Lyase / Drug Design / Emodin / Enzyme Inhibitors Limits: Humans Language: En Journal: Eur J Med Chem Year: 2017 Document type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: ATP Citrate (pro-S)-Lyase / Drug Design / Emodin / Enzyme Inhibitors Limits: Humans Language: En Journal: Eur J Med Chem Year: 2017 Document type: Article Affiliation country: United States