Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo
Copyright policy )Pharmacologic Inhibition of the Menin-MLL Interaction Blocks Progression of MLL Leukemia In Vivo
Chromosomal translocations affecting mixed lineage leukemia gene (MLL) 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 the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. Overall, we demonstrate 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.
- University of Michigan–Flint United States
- University of Michigan–Ann Arbor United States
- University of Pennsylvania United States
- Indiana University – Purdue University Indianapolis United States
- DePaul University United States
Cancer Research, Oncogene Proteins, Fusion, Drug Evaluation, Preclinical, Antineoplastic Agents, Cell Biology, Histone-Lysine N-Methyltransferase, Hematopoiesis, Mice, Inbred C57BL, Mice, Oncology, Proto-Oncogene Proteins, Disease Progression, Tumor Cells, Cultured, Animals, Humans, Female, metabolism, Myeloid-Lymphoid Leukemia Protein
Cancer Research, Oncogene Proteins, Fusion, Drug Evaluation, Preclinical, Antineoplastic Agents, Cell Biology, Histone-Lysine N-Methyltransferase, Hematopoiesis, Mice, Inbred C57BL, Mice, Oncology, Proto-Oncogene Proteins, Disease Progression, Tumor Cells, Cultured, Animals, Humans, Female, metabolism, Myeloid-Lymphoid Leukemia Protein
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