Drugs targeting SHIP2 demonstrate potent antiproliferative effects irrespective of SHIP2 inhibition.

The SH2-containing inositol 5'-phosphatase SHIP2 plays a crucial role in negative regulation of the PI3K/AKT signaling pathway. Putative small molecule inhibitors of SHIP2, AS1949490 and K149 have been reported to elicit a range of beneficial effects in treating or preventing obesity as well as killing cancer cells. However, whether these effects are direct results of SHIP2 inhibition has not been carefully assessed, e.g., in the absence of expression of the protein. Here, we show that these inhibitors alter the PI3K/AKT signaling pathway irrespective of SHIP2 protein expression. Moreover, we found that AS1949490 and K149 alter cell growth in normal and cancer cells lacking both SHIP1 and SHIP2. Overall, our data provide evidence that the antiproliferative effects of AS1949490 and K149 cannot be attributed to SHIP1/2 inhibition.