In vitro evaluation of a novel MEIS inhibitor reveals context-dependent anti-cancer activity in pancreatic cancer and leukemia cell lines

Targeting transcriptional regulators that coordinate oncogenic signaling and metabolic adaptation is an emerging strategy in cancer therapy. Here, we report in vitro anti-cancer effects of a novel small-molecule Myeloid Ecotropic Integration Site (MEIS) inhibitor, MEISi-2, previously identified through integrated in silico and in vitro screening approaches. MEISi-2 exhibited selective cytotoxicity in MEIS-expressing pancreatic cancer (PANC1, CFPAC1) and leukemia (RS-4;11, CCRF-CEM) cell lines, accompanied by robust induction of apoptosis and reactive oxygen species (ROS) generation. MEISi-2 showed potent anti-proliferative activity, with IC₅₀ values of 1.1 µM in leukemia cells and 7.7 µM in pancreatic cancer cells. Mechanistically, MEISi-2 treatment was associated with reduced expression of MEIS1 and MEIS2 and downregulated key metabolic enzymes involved in glycolysis and the pentose phosphate pathway, including LDHA (lactate dehydrogenase A), PGLS (6-phosphogluconolactonase), and G6PD (glucose-6-phosphate dehydrogenase). In leukemia models, MEISi-2 further reduced the expression of genes associated with stemness and self-renewal, such as DPYSL3 (Dihydropyrimidinase Like 3), DNMT3B (DNA Methyltransferase 3 Beta), ADGRG1 (Adhesion G Protein-Coupled Receptor G1), and MMRN1 (Multimerin 1). Collectively, these findings suggest that pharmacological inhibition of MEIS is associated with altered transcriptional and metabolic programs essential for cancer cell survival, identify MEIS as a potential transcriptional and metabolic vulnerability in MEIS-expressing leukemia and pancreatic cancer cells and support further in vitro and in vivo investigation of MEIS-targeted therapeutic strategies. MEIS inhibitors inhibited the growth of pancreatic cancer cell lines PANC1 and CFPAC1 and leukemia cell lines RS-4-11 and CCRF-CEM with high MEIS1, MEIS2, or MEIS3 content, achieving IC50 values as low as 1.1 µM. MEIS inhibitors led to increased reactive oxygen species (ROS) levels, correlating with enhanced apoptosis, particularly in MEIS+ pancreatic and leukemia cell lines, highlighting a potential mechanism of action for these inhibitors. MEIS inhibitors caused a substantial downregulation of MEIS1, MEIS2, and metabolism-associated genes such as LDHA, PGLS, G6PD in pancreatic and leukemia cells. MEIS inhibitors reduced the expression of critical leukemia-associated genes, including DPYSL3, DNMT3B, ADGRG1, and MMRN1 in RS-4;11.