NSUN1-17

NSUN1-17 is an AI-designed small-molecule inhibitor targeting the RNA cytosine methyltransferases NSUN1 (also known as NOL1 or NPO2) and NSUN2. Developed through a collaboration between the University of Chicago and Argonne National Laboratory, the compound was identified using supercomputing-driven structural prediction and functional screening of AI-designed drug libraries. NSUN1-17 is specifically intended to overcome resistance to venetoclax in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Its mechanism of action involves the disruption of NSUN1/2-mediated active chromatin structures (ACS) in the nucleus and translational complexes (TLC) in the ribosomes and mitochondria, which are critical for maintaining oncogenic transcription and translation. In preclinical studies, NSUN1-17 demonstrated the ability to efficiently eliminate AML cells from the blood vessels and lung parenchyma in syngeneic mouse models, and showed activity against human monocytic leukemia, erythroid leukemia, and lung cancer cell lines.