Antitumor activity and suppression of AKT pathway activation by PDK1 inhibitor SNS-391.

e13560 Background: 3-Phosphatidylinositide-dependent kinase 1 (PDK1) interacts with its substrate kinases after binding phosphatidylinositol (PI). PDK1 also affects downstream targets in a PI-independent manner, causing activation of additional pathways. PDK1 activation of AKT involves both PI-dependent and independent mechanisms, making PDK1 a challenging target for AKT pathway inhibition. Here we describe a novel PDK1 inhibitor, SNS-391, that is highly effective at inhibiting AKT activity with broad anti-tumor activity. Methods: SNS-391 was evaluated in the prostate cancer PC-3 cell line (PTEN null) for inhibition of several signaling pathways and was tested in proliferation assays in over 50 tumor cell lines of prostate, lung, colon, breast, melanoma, and pancreatic origin. Tumor xenograft studies were conducted in prostate, gastric, lung, pancreatic, and colorectal cancer models. Tumor samples were analyzed for pathway inhibition and compound exposure to develop PK/PD relationships. Results: SNS-391 (...