![]() ![]() On the basis of these observations, and the emerging role of C/EBPβ as a driver of diverse cancers, we sought to design a C/EBPβ antagonist peptide as a novel anticancer agent. Deletion of the C/EBPβ leucine zipper not only prevents dimerization and DNA binding but results in enhanced C/EBPβ ubiquitination and proteasomal degradation, suggesting that antagonism of dimerization represents a mechanism to negatively regulate their transcriptional activity ( 29). Dimerization allows for efficient interaction with key consensus DNA sequences as a precursor to regulate gene expression ( 27, 28). A hallmark of bZIP proteins are C-terminal α-helical leucine zipper domains that mediate interaction-specific homo- and heterodimerization, generating coiled-coil structures that typically stabilize interactions between adjacent basic amino acid-rich DNA-binding domains ( 26). Transcription factors such as those of the bZIP family have historically been considered “undruggable” due to their lack of enzymatic activity or a defined small-molecule binding site ( 24, 25). 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. ![]() Further, in mouse xenograft models ST101 exposure results in potent tumor growth inhibition or regression, both as a single agent and in combination studies. 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. ST101 exposure attenuates transcription of C/EBPβ target genes, including a significant decrease in expression of survival, transcription factors, and cell-cycle-related proteins. ST101 binds the leucine zipper domain of C/EBPβ, preventing its dimerization and enhancing ubiquitin-proteasome dependent C/EBPβ degradation. 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. 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. ![]() 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. ![]()
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