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MI-3454

Catalog No. T39584 CAS 2134169-43-8

MI-3454 is a highly potent, orally active, and selective inhibitor of the interaction between menin and MLL1, with an IC50 of 0.51 nM. This compound effectively inhibits the proliferation of leukemic cells and promotes their differentiation, leading to the regression or complete remission of leukemia in mouse models featuring MLL1 rearrangements or NPM1 mutations. This remarkable therapeutic effect is achieved through the downregulation of key genes involved in the development of leukemia.

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MI-3454, CAS 2134169-43-8

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Description	MI-3454 is a highly potent, orally active, and selective inhibitor of the interaction between menin and MLL1, with an IC50 of 0.51 nM. This compound effectively inhibits the proliferation of leukemic cells and promotes their differentiation, leading to the regression or complete remission of leukemia in mouse models featuring MLL1 rearrangements or NPM1 mutations. This remarkable therapeutic effect is achieved through the downregulation of key genes involved in the development of leukemia.
Targets&IC50	Menin-MLL1:0.51 nM (IC50)
In vitro	MI-3454, at concentrations ranging from 0.001 to 10 μM over a period of 7 days, significantly inhibits the proliferation of murine bone marrow cells transformed by MLL-AF9 or Hoxa9/Meis1. Additionally, a 50 nM concentration of MI-3454 administered for 6 days effectively downregulates the expression of HOXA9 and MEIS1 in human leukemic cell lines MV-4-11 and MOLM13. This compound demonstrates a marked decrease in the viability of leukemic cells containing various MLL fusion proteins (MLL-AF9, MLL-AF4, MLL-ENL), with GI50 values ranging from 7 to 27 nM. MI-3454 specifically disrupts the interaction between menin and a fragment of MLL1 (4–43), which includes the entire menin binding motif. Importantly, MI-3454 exhibits minimal inhibition of cytochromes P450, with less than 50% inhibition at 10 μM. In cell proliferation assays with murine bone marrow cells and RT-PCR analyses on MV-4-11 and MOLM13 cell lines, MI-3454 has shown considerable efficacy in reducing cell proliferation and downregulating not only HOXA9 and MEIS1 but also other genes associated with MLL fusions, such as MEF2C, DLX2, HOXA10, PBX3, and FLT3.
In vivo	MI-3454 effectively induces complete remission or halts the progression of leukemia in mouse models, including those with mixed lineage leukemia 1 (MLL1)-rearranged and nucleophosmin 1 (NPM1)-mutated subtypes. Administered orally at 120 mg/kg once or twice daily for seven days, or at 100 mg/kg twice daily for 19 days, MI-3454 significantly blocks leukemia advancement and, in the latter regimen, extends survival in MOLM13 xenotransplantation model mice. Similarly, in patient-derived xenograft (PDX) models of MLL leukemia, it achieves complete remission or impedes disease progression. Pharmacokinetic analysis shows MI-3454, given either as 100 mg/kg orally or 15 mg/kg intravenously, has a half-life of 3.2 hours with a peak concentration (Cmax) of 4698 mg/mL when administered orally. The compound also displays good stability in both murine and human liver microsomes and exhibits low penetration levels in the brain and cerebrospinal fluid, indicating a limited capacity to cross the blood-brain barrier.

Molecular Weight	636.74
Formula	C32H35F3N8OS
CAS No.	2134169-43-8

Storage

store at low temperature,store under nitrogen

Powder: -20°C for 3 years | In solvent: -80°C for 1 year

References and Literature

1. Szymon Klossowski, et al. Menin Inhibitor MI-3454 Induces Remission in MLL1 -rearranged and NPM1 -mutated Models of Leukemia. J Clin Invest. 2020 Feb 3;130(2):981-997.

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Please see Inhibitor Handling Instructions for more frequently ask questions. Topics include: how to prepare stock solutions, how to store products, and cautions on cell-based assays & animal experiments, etc.

Keywords

MI-3454 2134169-43-8 MI3454 MI 3454 inhibitor inhibit

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