Preclinical activity of investigational menin inhibitor DSP-5336 (Enzomenib)-based combinations against MLL1-rearranged (MLL-r) or mutant-NPM1 AML models
Abstract
MLL1 (KMT2A, or MLL1) is a transcriptional regulator and a histone-lysine-N-methyltransferase. The N-terminus of MLL1 binds to the scaffold protein Menin to form the Menin-MLL1 complex, which regulates the expression of the leukemogenic Homeobox A9 (HOXA9) gene and its co-factor MEIS1 in myeloid stem progenitor cells. In MLL1-rearranged (MLL-r) AML, which represents approximately 5-10% of AML, the N-terminus of the MLL1 protein fuses to the C-terminus of one of over 90 possible fusion partners, including AF4, AF9, ENL and ELL (~70% of MLL-r AML). This creates the MLL1 fusion proteins (MLL-FPs). The MLL-FP causes dysregulated gene expression of downstream HOXA genes and their co-factors MEIS1, PBX3, as well as of MEF2C and CDK6. In AML with mutant cytoplasmic NPM1 (mtNPM1c), Menin-MLL1 is the main oncogenic driver of HOXA9, MEIS1 and FLT3, and promotes self-renewal of myeloid progenitor cells. Previously reported preclinical data showed that treatment with Menin inhibitor (MI), e.g., SNDX-5613 (revumenib) or KO-539 (ziftomenib), disrupts binding of Menin to MLL1/2 and MLL1-FP, leading to reduced MLL1/2 and MLL1-FP target gene expression, as well as induction of differentiation and apoptosis in AML cells expressing MLL-FP or mtNPM1c. In clinical trials, MIs have exhibited encouraging activity with meaningful rates of objective remissions in patients with previously treated relapsed/refractory AML harboring MLLr or mtNPM1c. However, remission durations are short (4-7 months)…
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