Identification | Back Directory | [Name]
Formamide, N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indol-1-yl]methyl]bicyclo[1.1.1]pent-1-yl]- | [CAS]
2134169-43-8 | [Synonyms]
MI-3454 Formamide, N-[3-[[2-cyano-4-methyl-5-[[4-[[2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indol-1-yl]methyl]bicyclo[1.1.1]pent-1-yl]- | [Molecular Formula]
C32 H35 F3 N8 O S | [MOL File]
2134169-43-8.mol | [Molecular Weight]
636.73 |
Hazard Information | Back Directory | [Description]
MI-3454 is a 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. | [Uses]
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]. | [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.
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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.
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| [References]
[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. DOI:10.1172/JCI129126 |
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