MI-3454 是一种具有口服活性，高效和选择性的 Menin-MLL1 相互作用抑制剂，IC50 为 0.51 nM。MI-3454 通过下调涉及白血病发生的关键基因，在 MLL1 重排或 NPM1 突变的白血病小鼠模型中抑制细胞增殖，诱导分化并完全缓解或消退白血病。
货号:ajcx29504
CAS:2134169-43-8
分子式:C32H35F3N8OS
分子量：636.73
溶解度:N/A
纯度：98%
存储：Store at -20°C
库存：现货

Background:

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].

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

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]

[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.