Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity.
Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity.
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DOI：
10.18632/oncotarget.20200
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发表时间：
2017-09-19
期刊：
影响因子：
--
通讯作者：
Passaniti A
中科院分区：
文献类型：
--
作者：
Kim MS;Gernapudi R;Choi EY;Lapidus RG;Passaniti A
RUNX 2转录因子通过与多种激活或抑制靶基因的辅因子相互作用促进乳腺癌生长和转移。使用直接药物发现方法，我们将CADD 522鉴定为抑制runt box结构域蛋白RUNX 2的DNA结合的小分子。目前的研究定义了CADD 522对乳腺癌生长和转移的影响，并阐述了它发挥抗肿瘤活性的机制。CADD 522治疗导致乳腺癌细胞显着的生长抑制、克隆生存、肿瘤球形成和侵袭。CADD 522负调节RUNX 2靶基因如基质金属蛋白酶-13、血管内皮生长因子和葡萄糖转运蛋白-1的转录，但通过增加RUNX 2稳定性上调RUNX 2表达。CADD 522降低了RUNX 2介导的葡萄糖摄取增加，并降低了CBF-β和RUNX 2在S451残基处的磷酸化水平。这些结果表明，CADD 522对RUNX 2-DNA结合发挥抑制功能的几种潜在机制：干扰RUNX 2的DNA结合口袋，抑制葡萄糖摄取导致细胞周期停滞，下调CBF-β和减少S451-RUNX 2磷酸化。向MMTV-PyMT小鼠中施用CADD 522导致肿瘤发病率的显著延迟和肿瘤负荷的降低。在CADD 522治疗的人三阴性乳腺癌患者来源的异种移植模型中也观察到肿瘤体积显着减少。CADD 522在体内损害了乳腺癌细胞的肺滞留和生长，对小鼠没有明显的毒性。因此，通过抑制RUNX 2-DNA结合，CADD 522可能是一种潜在的抗肿瘤药物。
The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. Using a direct drug discovery approach we identified CADD522 as a small molecule that inhibits the DNA binding of the runt box domain protein, RUNX2. The current study defines the effect of CADD522 on breast cancer growth and metastasis, and addresses the mechanisms by which it exerts its anti-tumor activity. CADD522 treatment resulted in significant growth inhibition, clonogenic survival, tumorsphere formation, and invasion of breast cancer cells. CADD522 negatively regulated transcription of RUNX2 target genes such as matrix metalloproteinase-13, vascular endothelial growth factor and glucose transporter-1, but upregulated RUNX2 expression by increasing RUNX2 stability. CADD522 reduced RUNX2-mediated increases in glucose uptake and decreased the level of CBF-β and RUNX2 phosphorylation at the S451 residue. These results suggest several potential mechanisms by which CADD522 exerts an inhibitory function on RUNX2-DNA binding; interference with RUNX2 for the DNA binding pocket, inhibition of glucose uptake leading to cell cycle arrest, down-regulation of CBF-β, and reduction of S451-RUNX2 phosphorylation. The administration of CADD522 into MMTV-PyMT mice resulted in significant delay in tumor incidence and reduction in tumor burden. A significant decrease of tumor volume was also observed in a CADD522-treated human triple-negative breast cancer-patient derived xenograft model. CADD522 impaired the lung retention and outgrowth of breast cancer cells in vivo with no apparent toxicity to the mice. Therefore, by inhibiting RUNX2-DNA binding, CADD522 may represent a potential antitumor drug.
影响因子：
4
作者：
Pregizer, Steven;Baniwal, Sanjeev K.;Yan, Xiting;Brook, Zea;Frenkel, Baruch
通讯作者：
Frenkel, Baruch