Enhancing AML Differentiation with IMG-98: A Novel LSD1 Inhibitor in Combination with ATRA

Acute Promyelocytic Leukemia (APL) is a distinct type of acute myeloid leukemia (AML), marked by the presence of the PML-RARA fusion gene due to the t(15;17) translocation. Most individuals with this condition can be cured through therapies that include all-trans-retinoic acid (ATRA), which promotes the differentiation of cancerous cells. However, for those with non-APL AML, the prognosis is grim, with ATRA showing minimal effectiveness. Thus, expanding the reach of ATRA-based treatments is a significant research focus.

Our prior research on AML samples indicated a connection between the reduction of RARα2 levels and diminished H3K4me2 at the RARA2 promoter in AML cells compared to normal CD33+ cells. This promoter modification is linked to transcriptional activation. The enzyme LSD1, a demethylase that removes mono- and di-methyl groups from lysine residues, is found in high levels in AML patients and has been associated with tumor development. We hypothesized that inhibiting LSD1 with small molecules could enhance ATRA's differentiation effects in AML.

In our latest research, we evaluated several LSD-1 inhibitors, each demonstrating different levels of potency in biochemical assays. IMG-98, a novel inhibitor, was distinguished by its specificity, potency, and pharmacokinetic properties. It irreversibly binds to LSD1's FAD co-factor, as shown by fluorine nuclear magnetic resonance (fNMR) and fluorescence spectrophotometry, leading to significant structural changes in the enzyme. IMG-98 induced CD11b expression, a marker of differentiation, in AML cell lines and patient samples. It also showed strong anti-proliferative effects and hindered the growth of AML blast colonies. When combined with ATRA, IMG-98 reactivated differentiation pathways, leading to increased post-differentiation apoptosis compared to single-agent treatments. Gene expression analysis revealed that the combination of ATRA and IMG-98 upregulated genes related to myeloid differentiation.

Our findings suggest that combining ATRA with LSD1 inhibition could offer a new therapeutic approach for AML, promoting cell differentiation and inhibiting blast growth. A compound similar to IMG-98 is in late-stage preclinical development, with clinical trials expected to commence in 2016.