K118

K118 is a small molecule inhibitor of the Src homology 2-containing inositol 5'-phosphatase 1 (SHIP1), also known as INPP5D. It is being investigated as a novel therapeutic agent for pre-germinal center (pre-GC) B-cell malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), mantle cell lymphoma (MCL), and unmutated chronic lymphocytic leukemia (U-CLL). Unlike traditional kinase inhibitors that suppress oncogenic signaling, K118 works by inducing pathological PI3K hyperactivation. This hyperactivation mimics the signals that trigger central tolerance and negative selection in autoreactive B-cells, leading to the selective elimination of malignant B-cells that retain sensitivity to these developmental checkpoints. Preclinical studies have demonstrated that K118, particularly when used in sequential regimens with kinase inhibitors, can prolong survival in patient-derived xenograft (PDX) models of refractory B-ALL and MCL.