Jang Woo Dae, Lee Mi Young, Mun Jihye, Lim Gyutae, Oh Kwang-Seok
Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea.
Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 176 Gajeong-ro, Yuseong-gu, Daejeon 34129, Korea.
Biomedicines. 2022 Jul 11;10(7):1671. doi: 10.3390/biomedicines10071671.
The Forkhead box protein M1 (FoxM1) is an appealing target for anti-cancer therapeutics as this cell proliferation-associated transcription factor is overexpressed in most human cancers. FoxM1 is involved in tumor invasion, angiogenesis, and metastasis. To discover novel inhibitors that disrupt the FoxM1-DNA interaction, we identified CDI, a small molecule that inhibits the FoxM1-DNA interaction. CDI was identified through an assay based on the time-resolved fluorescence energy transfer response of a labeled consensus oligonucleotide that was bound to a recombinant FoxM1-dsDNA binding domain (FoxM1-DBD) protein and exhibited potent inhibitory activity against FoxM1-DNA interaction. CDI suppressed cell proliferation and induced apoptosis in MDA-MB-231 cells obtained from a breast cancer patient. Furthermore, it decreased not only the mRNA and protein expression of FoxM1 but also that of downstream targets such as CDC25b. Additionally, global transcript profiling of MDA-MB-231 cells by RNA-Seq showed that CDI decreases the expression of FoxM1-regulated genes. The docking and MD simulation results indicated that CDI likely binds to the DNA interaction site of FoxM1-DBD and inhibits the function of FoxM1-DBD. These results of CDI being a possible effective inhibitor of FoxM1-DNA interaction will encourage its usage in pharmaceutical applications.
叉头框蛋白M1（FoxM1）是抗癌治疗的一个有吸引力的靶点，因为这种与细胞增殖相关的转录因子在大多数人类癌症中都过表达。FoxM1参与肿瘤侵袭、血管生成和转移。为了发现破坏FoxM1与DNA相互作用的新型抑制剂，我们鉴定出了CDI，一种抑制FoxM1与DNA相互作用的小分子。CDI是通过基于与重组FoxM1-dsDNA结合结构域（FoxM1-DBD）蛋白结合的标记共有寡核苷酸的时间分辨荧光能量转移反应的测定法鉴定出来的，并且对FoxM1与DNA的相互作用表现出强大的抑制活性。CDI抑制了从一名乳腺癌患者获取的MDA-MB-231细胞的增殖并诱导其凋亡。此外，它不仅降低了FoxM1的mRNA和蛋白表达，还降低了诸如细胞周期蛋白依赖性激酶25B（CDC25b）下游靶点的表达。另外，通过RNA测序对MDA-MB-231细胞进行的全局转录谱分析表明，CDI降低了FoxM1调控基因的表达。对接和分子动力学模拟结果表明，CDI可能与FoxM1-DBD的DNA相互作用位点结合并抑制FoxM1-DBD的功能。CDI作为FoxM1与DNA相互作用的一种可能有效的抑制剂的这些结果将促进其在药物应用中的使用。
