Identification of a Unique Inhibitor-Binding Site on Choline Kinase α

Biochemistry. 2018 Feb 27;57(8):1316-1325. doi: 10.1021/acs.biochem.7b01257. Epub 2018 Feb 8.


Choline kinase α (ChoKα) is an enzyme that is upregulated in many types of cancer and has been shown to be tumorigenic. As such, it makes a promising target for inhibiting tumor growth. Though there have been several inhibitors synthesized for ChoKα, not all of them demonstrate the same efficacy in vivo, though the reasons behind this difference in potency are not clear. One particular inhibitor, designated TCD-717, has recently completed phase I clinical trials. Cell culture and in vitro studies support the powerful inhibitory effect TCD-717 has on ChoKα, but an examination of the inhibitor's interaction with the ChoKα enzyme has been missing prior to this work. Here we detail the 2.35 Å structure of ChoKα in complex with TCD-717. Examination of this structure in conjunction with kinetic assays reveals that TCD-717 does not bind directly in the choline pocket as do previously characterized ChoKα inhibitors, but rather in a proximal but novel location near the surface of the enzyme. The unique binding site identified for TCD-717 lends insight for the future design of more potent in vivo inhibitors for ChoKα.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Choline Kinase / antagonists & inhibitors*
  • Choline Kinase / chemistry*
  • Choline Kinase / metabolism
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*


  • Protein Kinase Inhibitors
  • CHKA protein, human
  • Choline Kinase