Anticancer Activity of ST101, A Novel Antagonist of CCAAT/Enhancer Binding Protein b

Emad Darvishi , Lila Ghamsari, Siok Leong, Ricardo Ramirez, Mark Koester, Erin Gallagher, Miao Yu, Jody Mason, Gene Merutka, Barry Kappel, Jim Rotolo

Research output: Contribution to journalArticlepeer-review

Abstract

CCAAT/enhancer binding protein β (C/EBPβ) is a basic leucine zipper (bZIP) family transcription factor, which is upregulated or overactivated in many cancers, resulting in a gene expression profile that drives oncogenesis. C/EBPβ dimerization regulates binding to DNA at the canonical TTGCGCAA motif and subsequent transcriptional activity, suggesting that disruption of dimerization represents a powerful approach to inhibit this previously “undruggable” oncogenic target. Here we describe the mechanism of action and antitumor activity of ST101, a novel and selective peptide antagonist of C/EBPβ that is currently in clinical evaluation in patients with advanced solid tumors. ST101 binds the leucine zipper domain of C/EBPβ, preventing its dimerization and enhancing ubiquitin-proteasome dependent C/EBPβ degradation. ST101 exposure attenuates transcription of C/EBPβ target genes, including a significant decrease in expression of survival, transcription factors, and cell-cycle-related proteins. The result of ST101 exposure is potent, tumor-specific in vitro cytotoxic activity in cancer cell lines including glioblastoma, breast, melanoma, prostate, and lung cancer, whereas normal human immune and epithelial cells are not impacted. Further, in mouse xenograft models ST101 exposure results in potent tumor growth inhibition or regression, both as a single agent and in combination studies. These data provide the First Disclosure of ST101, and support continued clinical development of ST101 as a novel strategy for targeting C/EBPβ-dependent cancers.

Original languageEnglish
Article numberMCT-21-0962
Pages (from-to)1632-1644
Number of pages13
JournalMolecular Cancer Therapeutics
Volume21
Issue number11
Early online date18 Sep 2022
DOIs
Publication statusPublished - Nov 2022

Keywords

  • Oncogenic transcription factors
  • signal transduction pathways
  • cell cycle
  • gene regulation
  • DRUG TARGETS
  • tumor suppressor
  • oncoprotein

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