Anticancer Activity of ST101, A Novel Antagonist of CCAAT/Enhancer Binding Protein β.
Anticancer Activity of ST101, A Novel Antagonist of CCAAT/Enhancer Binding Protein β.
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DOI：
10.1158/1535-7163.mct-21-0962
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发表时间：
2022-11-03
影响因子：
5.7
通讯作者：
Rotolo, Jim A.
中科院分区：
文献类型：
--
作者：
Darvishi, Emad;Ghamsari, Lila;Leong, Siok F.;Ramirez, Ricardo;Koester, Mark;Gallagher, Erin;Yu, Miao;Mason, Jody M.;Merutka, Gene;Kappel, Barry J.;Rotolo, Jim A.
CCAAT/增强子结合蛋白β（C/EBPβ）是一种碱性亮氨酸拉链（bZIP）家族转录因子，在许多癌症中上调或过度激活，导致基因反式激活，从而驱动肿瘤发生。C/EBPβ二聚化调节在典型TTGCGCAA基序处与DNA的结合和随后的转录活性，表明二聚化的破坏代表了抑制这种先前“不可治疗的”致癌靶点的有力方法。在这里，我们描述了ST 101的作用机制和抗肿瘤活性，ST 101是一种新型的选择性C/EBPβ肽拮抗剂，目前正在晚期实体瘤患者中进行临床评价。ST 101结合C/EBPβ的亮氨酸拉链结构域，阻止其二聚化并增强泛素-蛋白酶体依赖性C/EBPβ降解。ST 101暴露减弱了C/EBPβ靶基因的转录，包括存活、转录因子和细胞周期相关蛋白的表达显著降低。ST 101暴露的结果是在癌细胞系（包括胶质母细胞瘤、乳腺癌、黑素瘤、前列腺癌和肺癌）中具有有效的肿瘤特异性体外细胞毒性活性，而正常的人免疫和上皮细胞不受影响。此外，在小鼠异种移植模型中，ST 101暴露导致有效的肿瘤生长抑制或消退，无论是作为单一药剂还是在组合研究中。这些数据提供了ST 101的首次公开，并支持ST 101作为靶向C/EBPβ依赖性癌症的新策略的持续临床开发。
CCAAT/Enhancer Binding Protein β (C/EBPβ) is a basic leucine zipper (bZIP) family transcription factor that is upregulated or overactivated in many cancers, resulting in gene transactivation 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 anti-tumor 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, while 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.