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Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo

ABSTRACT: Chromosomal translocations affecting Mixed Lineage Leukemia (MLL) gene result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. Here we report development of novel, highly potent and orally bioavailable small molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, show their profound effects in MLL leukemia cells and substantial survival benefit in mice models of MLL leukemia. Finally, we demonstrate efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate for the first time that pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60673 | GEO | 2017/08/21

SECONDARY ACCESSION(S): PRJNA259220

REPOSITORIES: GEO

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Combination of SD70 and MI-503 exerts a synergistic effect against MLL:: AF9-driven AML

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Synergistic Targeting of FLT3 Mutations in AML via Combined Menin-MLL and FLT3 Inhibition

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