| Identification | Back Directory | [Name]
mi503 | [CAS]
1857417-13-0 | [Synonyms]
mi503
mi-503
CS-1946
MI503;MI 503
1-((1H-Pyrazol-4-yl)methyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-
1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- | [Molecular Formula]
C28H27F3N8S | [MDL Number]
MFCD28506303 | [MOL File]
1857417-13-0.mol | [Molecular Weight]
564.63 |
| Chemical Properties | Back Directory | [Boiling point ]
782.9±60.0 °C(Predicted) | [density ]
1.48±0.1 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO : 50 mg/mL (88.55 mM);Water : < 0.1 mg/mL (insoluble) | [form ]
Solid | [pka]
14.10±0.50(Predicted) | [color ]
White to off-white | [InChIKey]
DETOMBLLEOZTMZ-UHFFFAOYSA-N | [SMILES]
N1(CC2=CNN=C2)C2=C(C(C)=C(CN3CCC(NC4N=CN=C5SC(CC(F)(F)F)=CC5=4)CC3)C=C2)C=C1C#N |
| Hazard Information | Back Directory | [Uses]
MI-503 is used in the pharmacological inhibition of menin-MLL interaction that blocks progression of MLL leukemia in vivo. | [Biochem/physiol Actions]
MI-503 is a highly potent menin-MLL interaction inhibitor (cell-free IC50 = 14.7 nM against 1 nM FITC-MLL(4-13) peptide; cellular IC50 = 220 nM using HEK293 MLL-AF9 fusion transfectants) that targets menin MLL-binding site with high affinity (KD = 9.3 nM by ITC). MI-503 selectively inhibits mixed lineage leukemia (MLL) oncogenic fusion-driven cancer progression in cultures (GI50 from 250 to 570 nM; GI50 >5 μM against cells without MLL gene translocation) and is efficacious against human MLL leukemia MV4; tumor growth in mice in vivo (by 80-100%; 60 mg/kg/day i.p.) with good pharmacokinetic properties, oral bioavailability (73% post 30 mg/kg p.o.), and no adverse effects to the animals. | [in vitro]
MI-503 occupies the F9 and P13 pockets on menin, forming a hydrogen bond with Tyr276, and also extends beyond the P13 pocket to form hydrogen bonds with Trp341 and Glu366. Treatment of murine bone marrow cells (BMC) transformed with the mLL-AF9 oncogene with MI-503 results in substantial growth inhibition, with GI50 of 0.22 μM. The cell growth inhibitory effect of MI-503 is time-dependent, with a pronounced impact achieved after 7-10 days of treatment.
| [in vivo]
MI-503 achieves a high level in peripheral blood following a single intravenous or oral dose while also showing high oral bioavailability (75%). MI-503 induces strong tumor growth inhibition with once-daily intraperitoneal (i.p.) administration. Treatment with MI-503 results in an over 80% reduction in MV4, 11 tumor volume, and complete tumor regression in two mice. Ten consecutive days of treatment with MI-503 results in a marked delay in the progression of mLL leukemia in mice and significantly reduces leukemia tumor burden. Treatment with MI-503 and MI-463 leads to markedly reduced expression of Hoxa9 and Meis1, downstream targets of mLL fusion proteins substantially upregulated in mLL leukemias.
| [storage]
Store at -20°C |
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