Mechanistic insights into the activation of ester prodrugs of 666-15

Fuchun Xie, Pedro Martín-Acosta, Bingbing X. Li, Xiangshu Xiao

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


cAMP-response element binding protein (CREB) is an oncogenic transcription factor implicated in many different types of cancer. We previously reported the discovery of 666-15 as a potent inhibitor of CREB-mediated gene transcription. In an effort to improve the aqueous solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 instead of a long-range O,N-acyl transfer reaction that was initially proposed. These results provide unique insights into the activation of these ester prodrugs.

Original languageEnglish (US)
Article number127455
JournalBioorganic and Medicinal Chemistry Letters
Issue number19
StatePublished - Oct 1 2020


  • CREB
  • Cancer
  • Inhibitor
  • Prodrug
  • Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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