Menin is an epigenetic scaffold protein known to regulate pathogenic gene expression in several cell types. Genetic menin loss (MEN1 Syndrome) is associated with insulinemia due to upregulated pancreatic β-cell proliferation. Ziftomenib is a potent and selective menin inhibitor currently in clinical trials for the treatment of acute leukemias. Zucker Diabetic Fatty rats were used to assess the antidiabetic activity of ziftomenib dosed orally once daily for 27 days. Ziftomenib treatment was well tolerated and rapidly reduced fasting blood glucose (FBG) levels, with normalization of FBG levels observed in most animals within 2 weeks. Ziftomenib also progressively reduced %HbA1C by an average of 1.49% by week 4 (FIG). Oral glucose tolerance tests demonstrated that ziftomenib-treated animals achieved significantly improved postprandial glucose control (P<0.0001). Ziftomenib induced a reduction in HOMA-IR within 1 week, suggesting that one of the effects of menin inhibition is acute sensitization of the animals to insulin. In addition, fasting insulin and c-peptide levels demonstrated that ziftomenib significantly stimulated insulin production at week 3-4 (FIG). These observations suggest that pharmacological targeting of menin may be a viable option to treat both insulin resistance and insulin insufficiency, the two main pathological features of T2DM.
A. McCloskey: None. Y.A. Liu: None. X. Wang: None. F. Burrows: None.
