IACS-17817

IACS-17817 is a highly selective small molecule catalytic inhibitor of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), also known as WHSC1 or MMSET. NSD2 is a histone methyltransferase that specifically dimethylates histone H3 at lysine 36 (H3K36me2), a chromatin mark associated with transcriptional activation and oncogenic signaling. Dysregulation of NSD2, through overexpression or activating mutations (such as the E1099K mutation found in pediatric ALL), is a known driver in various malignancies, including multiple myeloma, acute lymphoblastic leukemia (ALL), and several solid tumors. IACS-17817 works by binding to the catalytic domain of NSD2, thereby reducing global H3K36me2 levels and inducing chromatin reprogramming that suppresses tumor cell proliferation and survival. Preclinical evidence supports its potential in head and neck squamous cell carcinoma (HNSCC), pancreatic cancer, and lung cancer, both as a monotherapy and in combination with other agents such as PARP inhibitors.