MM-102 is a high-affinity, cell-permeable peptidomimetic that functions as a potent inhibitor of the MLL1-WDR5 protein-protein interaction, with an IC₅₀ of 2.4nM and a Ki<1nM[1-2]. MM-102 inhibits histone H3K4 methyltransferase activity by blocking the binding of WDR5 to the MLL1 complex. MM-102 is utilized in research areas such as leukemia and renal fibrosis[3-4].
In vitro, treatment of human cholangiocarcinoma cells (TFK1 and RBE) with MM-102 (50μM) for 24 hours. MM-102 significantly inhibited the interaction between WDR5 and KMT2A, downregulated ABCB1 expression, and enhanced the sensitivity of the cholangiocarcinoma cells to cisplatin, while also inhibiting cell proliferation and migration capabilities[5]. MM-102 (300pM) was used to treat synovial fibroblasts (RASFs) derived from patients with rheumatoid arthritis (RA) for 72 hours. MM-102 significantly reduced the levels of H3K4 trimethylation (H3K4me3) in the promoter regions of specific chemokine genes (CCL5, CXCL9, CXCL10, CXCL11) and correspondingly decreased the mRNA expression levels of these chemokine genes[6].
In vivo, in a mouse model of renal ischemia-reperfusion injury (IRI), intraperitoneal administration of MM-102 (15mg/kg/day) for 7 consecutive days, starting from the day of surgery, MM-102 significantly suppressed the expression of MLL1, WDR5, and H3K4me3, reduced the accumulation of p16INK4a-positive cells, and alleviated renal fibrosis, inflammatory responses, and cellular senescence-related pathological changes[7]. In a methylglyoxal (MGO)-induced peritoneal fibrosis mouse model using C57BL/6J mice, intraperitoneal administration of MM-102 (10mg/kg) for 3 weeks. MM-102 significantly attenuated MGO-induced peritoneal fibrosis, inflammation, and functional impairment[8].
References:
[1] Karatas H, Townsend EC, Cao F, et al. High-affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J Am Chem Soc. 2013 Jan 16;135(2):669-82.
[2] Zhang Z, Zhai Y, Ma X, et al. Down-Regulation of H3K4me3 by MM-102 Facilitates Epigenetic Reprogramming of Porcine Somatic Cell Nuclear Transfer Embryos. Cell Physiol Biochem. 2018;45(4):1529-1540.
[3] Liu C, Qiu S, Li W, et al. MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-Atf4-Chop and PI3K/Akt-Lrp1 signaling pathway. Chin Med J (Engl). 2025 Jul 10.
[4] Koch MS, Deo M, Schmidt C, et al. KMT2A is a prerequisite of malignant transformation during IDH-mutant gliomagenesis. Neuro Oncol. 2026 Jan 14:noag006.
[5] Wang D, Chen J, Wu G, et al. MBD2 regulates the progression and chemoresistance of cholangiocarcinoma through interaction with WDR5. J Exp Clin Cancer Res. 2024 Sep 30;43(1):272.
[6] Okamoto K, Araki Y, Aizaki Y, et al. Regulation of cytokine and chemokine expression by histone lysine methyltransferase MLL1 in rheumatoid arthritis synovial fibroblasts. Sci Rep. 2024 May 9;14(1):10610.
[7] Shimoda H, Doi S, Nakashima A, et al. Inhibition of the H3K4 methyltransferase MLL1/WDR5 complex attenuates renal senescence in ischemia reperfusion mice by reduction of p16INK4a. Kidney Int. 2019 Nov;96(5):1162-1175.
[8] Hara D, Sasaki K, Doi S, et al. Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a. FASEB J. 2025 Apr 30;39(8):e70543.
MM-102是一种高亲和性、细胞通透性的肽模拟物，作为MLL1-WDR5蛋白相互作用的有效抑制剂，IC₅₀为2.4nM，Ki<1nM[1-2]。MM-102通过阻断WDR5与MLL1复合物的结合，抑制组蛋白H3K4甲基转移酶活性。MM-102可用于白血病和肾纤维化等相关研究[3-4]。
在体外，MM-102（50μM）处理人胆管癌细胞（TFK1和RBE）24小时，MM-102显著抑制WDR5与KMT2A的相互作用，降低ABCB1的表达，并增强胆管癌细胞对顺铂的敏感性，同时抑制细胞增殖和迁移能力[5]。MM-102（300pM）处理源自类风湿关节炎（RA）患者的滑膜成纤维细胞（RASFs）72小时。MM-102显著降低了特定趋化因子基因（CCL5、CXCL9、CXCL10、CXCL11）启动子区域的H3K4三甲基化（H3K4me3）水平，并相应地降低了这些趋化因子基因的mRNA表达水平[6]。
在体内，在肾脏缺血再灌注损伤（IRI）小鼠模型中，MM-102（15mg/kg/day）腹腔注射处理（从手术后开始连续7天），MM-102显著抑制MLL1、WDR5和H3K4me3的表达，降低p16INK4a阳性细胞积累，减轻肾脏纤维化、炎症反应和细胞衰老相关病理变化[7]。MM-102（10mg/kg）通过腹腔注射给药，用于处理经甲基乙二醛（MGO）诱导的腹膜纤维化C57BL/6J小鼠模型，持续3周。MM-102显著减轻了MGO诱导的腹膜纤维化、炎症和功能损伤[8]。