| References: |
MI-503 is a highly potent and orally bioavailable small molecule inhibitor of the menin-MLL interaction.
InVitro: 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 effect achieved after 7-10 days of treatment.
InVivo: 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, downstream targets of MLL fusion proteins substantially upregulated in MLL leukemias. |
