Longevity & AgingTwo leukemia drug targets, PRMT5 and LSD1, team up to push AML cells to differentiate and die
Acute myeloid leukemia (AML) cells fail to mature and keep multiplying. Researchers ran a chemical screen for drugs that work with PRMT5 inhibition, which is effective against AML but toxic when pushed too far. They found that LSD1 inhibitors synergize strongly with PRMT5 inhibitors in several AML cell lines and in mice. Together the drugs triggered myeloid differentiation, slowed cell division, and induced apoptosis that depended on p53. PRMT5 inhibition altered splicing of MDM4, which raised p53 activity, while LSD1 inhibition mainly changed gene expression. The team then built six first-in-class hybrid molecules that block both enzymes. The lead compound, MC4455, reproduced the combination's effects on gene expression, splicing, and differentiation in cells. These results are preclinical, but they point toward a new way to treat AML.
