MLL1 (Mixed lineage leukemia 1) is a H3K4 methyltransferase and targeting its enzymatic activity, further as being driven by MLL1/WDR5 protein-protein interaction, has been proposed as a novel therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion proteins. MM-102 is a peptidomimetic MLL1 antagonist which can disrupt the MLL1/WDR5 interaction with Ki value < 1 nM for binding to WDR5. MM-102 at concentration of 50μM could significantly decrease the expression of HoxA9 and Meis-1, two critical MLL1 target genes in MLL1 fusion protein mediated leukemogenesis, in bone marrow cells transduced with MLL1-AF9 fusion construct post 96-hour treatment. Also, it dose-dependently and selectively inhibited MV4;11 and KOPN8 cell line carrying MLL1-AF4 and MLL1-ENL fusion proteins, respectively, at concentration ranging in 25-100μM for 7 days with apoptosis observed, but not K562 leukemia cell line. Adding MM-102 at concentration of 75μM into somatic cell nuclear transfer embryos culture system could greatly improve porcine somatic cell nuclear transfer effciency and blastocyst quality to make them more similar to in vivo embryos. This may due to the rescue of aberrant gene expression patterns of a series of epigenetic chromatin modifcation enzymes, pluripotent and apoptotic genes at the zygotic gene activation and blastocyst stages through down-regulation of H3K4me3 with MM-102.
MM-102 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Recombinant H3 protein
1.6 µM
2 hours
To study the inhibitory effect of MM-102 on MLL1 methyltransferase activity. Results showed that MM-102 efficiently inhibited the activity of wild-type MLL1, but had no inhibitory effect on the R3864C and R3841W mutants.
Mol Oncol. 2017 Apr;11(4):373-387.
Primary chondrocytes
20 µM
24 hours
MM-102 pretreatment effectively rescued the negative impact of FSS on chondrocytes, which may lay a foundation of epigenetic-based therapy on OA.
J Inflamm Res. 2021 Nov 19;14:6067-6083.
HEK293 cells
0.8 µM
3 hours
To study the interaction of MLL1 with the WRA complex and its methyltransferase activity. Results showed that MLL1 activity was significantly enhanced in the presence of the WRA complex.
Mol Oncol. 2017 Apr;11(4):373-387.
MV4;11 cells
25 µM, 50 µM
7 days
MM-102 dose-dependently inhibits cell growth in the MV4;11 and KOPN8 leukemia cell lines, completely inhibiting cell growth at 75 μM.
J Am Chem Soc. 2013 Jan 16;135(2):669-82.
K562 cells
50 µM, 75 µM
7 days
In the K562 leukemia cell line, MM-102 has no significant effect at 50 μM and only minimal effect at 75 μM.
J Am Chem Soc. 2013 Jan 16;135(2):669-82.
RA synovial fibroblasts
300 pM
72 hours
To investigate the effect of MM-102 on H3K4me3 and mRNA levels in RA synovial fibroblasts, the results showed that MM-102 significantly reduced H3K4me3 and mRNA levels of CCL5, CXCL9, CXCL10, and CXCL11 genes.
Sci Rep. 2024 May 9;14(1):10610.
Bovine embryonic stem cells (bESCs)
50 µM
MLL1 inhibition improved the pluripotency and differentiation potential of bESCs via the up-regulation of stem cell signaling pathways such as PI3K-Akt and WNT.
Int J Mol Sci. 2023 Jul 25;24(15):11901.
TFK1 cells
50 µM
MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin.
J Exp Clin Cancer Res. 2024 Sep 30;43(1):272.
RBE cells
50 µM
MM-102 inhibited the expression of ABCB1 in CCA cells and decreased the chemoresistance of CCA to cisplatin.
J Exp Clin Cancer Res. 2024 Sep 30;43(1):272.
MM-102 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Primary CCA mouse model
Intraperitoneal injection
15 mg/kg
Once daily for 7 days
MM-102 significantly suppressed the proliferation, migration and chemoresistance of CCA cells, increasing the sensitivity of CCA to cisplatin.
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