化合物 MI-3454 T39584

Product Introduction
Bioactivity


英文名: MI-3454

描述: 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.

体外活性: 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 GI 50 values ranging from 7 to 27 nM. MI-3454 blocks the interaction of menin with an MLL1 4–43 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 .

体内活性: 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 T 1/2 of 3.2 hours, a C max of 4698 mg/mL for PO[1]. MI-3454 exhibits favorable stability in murine and human liver microsomes (t 1/2 =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 T 1/2 of 3.2 hours, a C max of 4698 mg/mL for PO. Had a T 1/2 of 2.4 hours, a CL of 2375 mL/hours?kg, and a V ss of 5358 mL/kg for IV.

存储条件: store at low temperature,store under nitrogenPowder: -20°C for 3 years | In solvent: -80°C for 1 year

关键字: MI3454 | MI-3454 | MI 3454

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注：该产品未在中华人民共和国食品药品监督管理部门申请医疗器械注册和备案，不可用于临床诊断或治疗等相关用途