Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase

Steffi K Koerner; Jun-Ichi Hanai; Sha Bai; Finith E Jernigan; Miwa Oki; Chieko Komaba; Emi Shuto; Vikas P Sukhatme; Lijun Sun

doi:10.1016/j.ejmech.2016.12.018

Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase

Eur J Med Chem. 2017 Jan 27:126:920-928. doi: 10.1016/j.ejmech.2016.12.018. Epub 2016 Dec 9.

Authors

Steffi K Koerner¹, Jun-Ichi Hanai², Sha Bai¹, Finith E Jernigan¹, Miwa Oki³, Chieko Komaba³, Emi Shuto³, Vikas P Sukhatme⁴, Lijun Sun⁵

Affiliations

¹ Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
² 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.
³ Divisions of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁴ 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.
⁵ 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.

PMID: 27997879
DOI: 10.1016/j.ejmech.2016.12.018

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.

Keywords: ATP citrate lyase inhibitor; Cancer stem cell; Emodin anthraquinones and anthracenone; Lipogenesis.

MeSH terms

ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
ATP Citrate (pro-S)-Lyase / chemistry
ATP Citrate (pro-S)-Lyase / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Chemistry Techniques, Synthetic
Drug Design*
Emodin / chemical synthesis*
Emodin / chemistry
Emodin / metabolism
Emodin / pharmacology*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Neoplastic Stem Cells / drug effects
Protein Domains
Structure-Activity Relationship

Substances

Enzyme Inhibitors
ATP Citrate (pro-S)-Lyase
Emodin