X-ray crystallography of Epacadostat in adduct with Carbonic Anhydrase IX

Bioorg Chem. 2020 Apr:97:103669. doi: 10.1016/j.bioorg.2020.103669. Epub 2020 Feb 14.

Abstract

Epacadostat (EPA), a new and promising anti-cancer small molecule is firmly established as selective inhibitor of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). The X-Ray structure of the human CA IX mimic in complex with EPA is investigated here for the first time and compared to previously reported EPA-CA II adduct. The structural information obtained are all in agreement with the in vitro kinetic data which accounted for a selective inhibition of the CA IX over the CA II isoform.

Keywords: Carbonic Anhydrase inhibitor; Carbonic Anhydrases IX; Check point inhibitor; Epacadostat; Metalloenzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / chemistry
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Carbonic Anhydrase IX / antagonists & inhibitors
  • Carbonic Anhydrase IX / chemistry
  • Carbonic Anhydrase IX / metabolism*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Crystallography, X-Ray
  • Humans
  • Molecular Docking Simulation
  • Oximes / chemistry*
  • Oximes / pharmacology*
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Oximes
  • Sulfonamides
  • epacadostat
  • CA9 protein, human
  • Carbonic Anhydrase IX