Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4787-4792. doi: 10.1016/j.bmcl.2015.07.018. Epub 2015 Jul 14.


Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications.

Keywords: Covalent; Erastin; Ferroptosis; Metabolic stability; Reactive carbonyl.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Ketones / chemistry*
  • Ketones / metabolism
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / pharmacology
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Solubility
  • Structure-Activity Relationship
  • Water / chemistry*


  • Ketones
  • Piperazines
  • Small Molecule Libraries
  • erastin
  • Water