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Sumitomo - Model DSP-5336 - Menin-MLL Binding Inhibitor
DSP-5336 is a small molecule inhibitor against the binding of menin and mixed-lineage leukemia (MLL) protein. Menin is a scaffold nuclear protein that plays various key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and hematopoiesis.26,27 Binding of menin to MLL fusion and wildtype proteins leads to the upregulation of HOXA family and MEIS1 genes that function to stall myeloid cellular differentiation and induce leukemogenic transformation.26,28,29 Preclinical evidence shows that the disruption of fusion and wild-type menin-MLL interactions inhibits leukemic cell proliferation and restores terminal differentiation of MLL-rearranged and nucleophosmin 1 (NPM1)–mutated leukemic cells.26,30
Understanding our target
Patients with acute myeloid or lymphoblastic leukemias (AML or ALL) harboring MLL translocations have a very unfavorable prognosis and respond poorly to available treatments.34 Further, NPM1 mutations are prevalent in adult AML, demonstrating the high need for new therapies that target these leukemogenic variants. Menin is involved in multiple protein-protein interactions, each with unique structural binding affinity and resultant gene transactivation or repression.29,35 Inhibition of menin interaction with MLL proteins downregulates target genes, including HOXA9 and MEIS1, which are known to result in enhanced cellular proliferation and blockage of hematopoietic differentiation, ultimately leading to acute leukemia.29,36 Translocations of the MLL gene and NPM1 mutations are associated with the upregulated expression of HOXA and MEIS1 genes.33,37
Preclinical evidence
DSP-5336 has shown selective growth inhibition in human acute leukemia cell lines with MLL rearrangements or NPM1 mutations, both of which rely on the menin-MLL interaction for upregulation of genes instrumental to leukemogenesis.29,33
Clinical development
DSP-5336 is currently being investigated in a phase I/II study in adult acute leukemia patients with and without MLL rearrangement or NPM1 mutation.
