MI-503 是一种高效且可口服的 menin-mLL 相互作用抑制剂。

MI-503 is a highly effective and orally bioavailable inhibitor of the menin-mLL interaction.

Treatment of murine bone marrow cells (BMC) transformed with the mLL-AF9 oncogene with MI-503 results in substantial growth inhibition (GI50: 0.22 μM). The cell growth inhibitory effect of MI-503 is time-dependent, with a pronounced effect achieved after 7-10 days of treatment.

MI-503 achieves high level in peripheral blood following a single intravenous or oral dose, while also showing high oral bioavailability (75%). MI-503 induces strong inhibition of tumor growth 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 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.

Leukemia cells are treated with MI-503 or 0.25% DMSO and cultured at 37 °C for 7 days. Media is changed on day 4, viable cell numbers are restored to the original concentration and MI-503 are re-supplied. MTT cell proliferation assay kit is then employed, and plates are read for absorbance at 570 nm using a microplate reader.

For efficacy studies in MV4;11 subcutaneous xenograft mice model, 5×10^6 cells are injected into the 4-6 week old female BALB/c nude mice. Treatment is started when the tumor size reached ~100 mm^3. Vehicle (25% DMSO, 25% PEG400, 50% PBS) or compounds (MI-463 or MI-503) are administrated once daily at designated doses using i.p. injections.

1857417-13-0

C28H27F3N8S

564.63

DMSO:45 mg/mL (79.7 mM),Need ultrasonic
H2O:Insoluble
Powder: -20°C for 3 years
In solvent: -80°C for 2 years