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  3. MI-3454

MI-3454 

Cat. No.: HY-136360
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MI-3454 is an orally active, highly potent and selective menin-MLL1 interaction inhibitor with an IC50 of 0.51 nM. MI-3454 inhibits proliferation, induces differentiation and complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia through downregulation of key genes involved in leukemogenesis.

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MI-3454 Chemical Structure

MI-3454 Chemical Structure

CAS No. : 2134169-43-8

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Description

MI-3454 is an orally active, highly potent and selective menin-MLL1 interaction inhibitor with an IC50 of 0.51 nM. MI-3454 inhibits proliferation, induces differentiation and complete remission or regression of leukemia in mouse models of MLL1-rearranged or NPM1-mutated leukemia through downregulation of key genes involved in leukemogenesis[1].

IC50 & Target

IC50: 0.51 nM (menin-MLL1 interaction)[1]

In Vitro

MI-3454 (0.001-10 μM; 7 days) strongly reduces murine bone marrow cells transformed with MLL-AF9 or Hoxa9/Meis1 proliferation[1].
MI-3454 (50 nM; 6 days) leads to downregulated expression of HOXA9 and MEIS1 in Human leukemic cell lines MV-4-11 cells or MOLM13[1].
MI-3454 markedly reduces the viability of leukemic cells harboring various MLL fusion proteins (MLL-AF9, MLL-AF4, MLL-ENL), with GI50 values ranging from 7 to 27 nM. MI-3454 blocks the interaction of menin with an MLL14–43 fragment encompassing the entire menin binding motif[1].
MI-3454 does not potently inhibit cytochromes P450 (<50% inhibition at 10 μM)[1].

Cell Proliferation Assay[1]

Cell Line: Murine bone marrow cells transformed with MLL-AF9 or Hoxa9/Meis1
Concentration: 0.001, 0.01, 0.1, 1, 10 μM
Incubation Time: 7 days
Result: Demonstrated strong reduction of cell proliferation.

RT-PCR[1]

Cell Line: Human leukemic cell lines MV-4-11 cells or MOLM13
Concentration: 50 nM
Incubation Time: 6 days
Result: Led to downregulated expression of HOXA9 and MEIS1 and expression level of other MLL fusion target genes, including MEF2C, DLX2, HOXA10, PBX3, and FLT3.
In Vivo

MI-3454 induces complete remission or regression of leukemia in mouse models of mixed lineage leukemia 1 (MLL1)-rearranged or nucleophosmin 1 (NPM1)-mutated leukemia[1].
MI-3454 (p.o.; 120 mg/kg; one or twice daily for 7 consecutive days) sufficiently blocks leukemia progression by a once-daily treatment[1].
MI-3454 (p.o.; 100 mg/kg; b.i.d.; for 19 consecutive days) effectively blocks leukemia progression during the treatment period and markedly prolongs survival of MOLM13 xenotransplantation model mice. MI-3454 induces complete remission or blocks leukemia progression in patient-derived xenograft (PDX) models of MLL leukemia[1].
MI-3454 (100 mg/kg of PO or 15 mg/kg of IV) has a T1/2 of 3.2 hours, a Cmax of 4698 mg/mL for PO[1].
MI-3454 exhibits favorable stability in murine and human liver microsomes (t1/2=20.4 minutes and 37.1 minutes, respectively)[1].
MI-3454 demonstrates lower levels in brain and cerebrospinal fluid, suggesting limited ability to cross the blood-brain barrier[1].

Animal Model: 8- to 10-week-old female NSG mice (MV-4-11 xenotransplantation model of MLL leukemia)[1]
Dosage: 120 mg/kg
Administration: Orally; one or twice daily for 7 consecutive days
Result: A once-daily treatment was sufficient to block leukemia progression.
Animal Model: Female CD-1 mice[1]
Dosage: 100 mg/kg (PO) or 15 mg/kg (IV) (Pharmacokinetic Analysis)
Administration: PO or IV
Result: Had a T1/2 of 3.2 hours, a Cmax of 4698 mg/mL for PO.
Had a T1/2 of 2.4 hours, a CL of 2375 mL/hours•kg, and a Vss of 5358 mL/kg for IV.
Molecular Weight

636.73

Formula

C₃₂H₃₅F₃N₈OS

CAS No.

2134169-43-8

SMILES

O=CNC1(C2)CC2(CN3C(C#N)=CC4=C3C=CC(CN5CCC(NC6=C(C=C(CC(F)(F)F)S7)C7=NC(NC)=N6)CC5)=C4C)C1

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

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Keywords:

MI-3454MI3454MI 3454Epigenetic Reader Domainorallymenin-MLL1interactionproliferationdifferentiationleukemiaMLL1NPM1leukemogenesisMV-4-11MOLM13Inhibitorinhibitorinhibit

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