Lu Kebin, Tao He, Si Xiaomin, Chen Qingjuan
Department of Paediatrics, Shan Xian Central Hospital, Heze, China.
Department of Medical Oncology, Shan Xian Haijiya Hospital, Heze, China.
Front Oncol. 2018 Nov 14;8:502. doi: 10.3389/fonc.2018.00502. eCollection 2018.
The histone H3 lysine 4 (H3K4) presenter WDR5 forms protein complexes with H3K4 methyltransferases MLL1-MLL4 and binding partner proteins including RBBP5, ASH2L, and DPY30, and plays a key role in histone H3K4 trimethylation, chromatin remodeling, transcriptional activation of target genes, normal biology, and diseases such as MLL-rearranged leukemia. By forming protein complexes with other proteins such as Myc, WDR5 induces transcriptional activation of key oncogenes, tumor cell cycle progression, DNA replication, cell proliferation, survival, tumor initiation, progression, invasion, and metastasis of cancer of a variety of organ origins. Several small molecule MLL/WDR5 protein-protein interaction inhibitors, such as MM-401, MM-589, WDR5-0103, Piribedil, and OICR-9429, have been confirmed to reduce H3K4 trimethylation, oncogenic gene expression, cell cycle progression, cancer cell proliferation, survival and resistance to chemotherapy without general toxicity to normal cells. Derivatives of the MLL/WDR5 interaction inhibitors with improved pharmacokinetic properties and bioavailability are expected to have the potential to be trialed in cancer patients.
组蛋白H3赖氨酸4（H3K4）呈递蛋白WDR5与H3K4甲基转移酶MLL1 - MLL4以及包括RBBP5、ASH2L和DPY30在内的结合伴侣蛋白形成蛋白质复合物，并在组蛋白H3K4三甲基化、染色质重塑、靶基因转录激活、正常生物学过程以及诸如MLL重排白血病等疾病中发挥关键作用。通过与Myc等其他蛋白形成蛋白质复合物，WDR5诱导关键癌基因的转录激活、肿瘤细胞周期进程、DNA复制、细胞增殖、存活、肿瘤起始、进展、侵袭以及多种器官起源癌症的转移。几种小分子MLL/WDR5蛋白 - 蛋白相互作用抑制剂，如MM - 401、MM - 589、WDR5 - 0103、吡贝地尔和OICR - 9429，已被证实可降低H3K4三甲基化、致癌基因表达、细胞周期进程、癌细胞增殖、存活以及对化疗的耐药性，且对正常细胞无一般毒性。具有改善药代动力学性质和生物利用度的MLL/WDR5相互作用抑制剂衍生物有望有潜力在癌症患者中进行试验。
