Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening

Finith E Jernigan; Jun-Ichi Hanai; Vikas P Sukhatme; Lijun Sun

doi:10.1016/j.bmcl.2017.01.001

Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening

Bioorg Med Chem Lett. 2017 Feb 15;27(4):929-935. doi: 10.1016/j.bmcl.2017.01.001. Epub 2017 Jan 16.

Authors

Finith E Jernigan¹, Jun-Ichi Hanai², Vikas P Sukhatme³, Lijun Sun⁴

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 Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
³ Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
⁴ 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: 28129980
DOI: 10.1016/j.bmcl.2017.01.001

Abstract

The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC₅₀ of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer.

Keywords: ATP citrate lyase inhibitor; Cancer metabolism; Cancer stemness; Furoic acid; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Cell Line
Drug Discovery
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Furans / chemistry*
High-Throughput Screening Assays
Humans
Molecular Docking Simulation
Molecular Structure

Substances

Carboxylic Acids
Enzyme Inhibitors
Furans
ATP Citrate (pro-S)-Lyase