MI-3454 is an orally active, highly potent and selective menin-MLL1 interaction inhibitor with an IC 50 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 In Vitro MI-3454 (0.001-10 μM; 7 days) strongly reduces murine bone marrow cells transformed with MLL-AF9 or Hoxa9/Meis1 proliferation. 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. 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. MI-3454 does not potently inhibit cytochromes P450 ( 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 . MI-3454 (p.o.; 120 mg/kg; one or twice daily for 7 consecutive days) sufficiently blocks leukemia progression by a once-daily treatment . 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 . 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 . MI-3454 exhibits favorable stability in murine and human liver microsomes (t 1/2 =20.4 minutes and 37.1 minutes, respectively) . MI-3454 demonstrates lower levels in brain and cerebrospinal fluid, suggesting limited ability to cross the blood-brain barrier . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: 8- to 10-week-old female NSG mice (MV-4-11 xenotransplantation model of MLL leukemia) 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 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. Form:Solid IC50& Target:IC50: 0.51 nM (menin-MLL1 interaction)