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.