SHIPi improves hematologic recovery after chemotherapy.

The use of recombinant growth factors has led to improved hematopoietic function after chemotherapy, but hematologic and immune complications still occur after chemotherapy which can be life-threatening. Here we show that pan-SHIPi compounds can induce endogenous G-CSF and TPO production in vivo and can also increase host survival after a lethal fungal challenge. In addition, we show that consistent with their ability to induce G-CSF, pan-SHIPi compounds can promote increased granulopoiesis in normal mice and speed recovery of neutrophil counts after chemotherapy. We also report the identification of a novel SHIP1-selective inhibitor, A32, that also increases steady state production of both G-CSF and TPO. These findings indicate small molecule inhibitors of SHIP1 can promote hematologic recovery after myeloablative chemotherapy and are a unique means to induce endogenous production of multiple growth factors that promote hematologic recovery.