Targeting PDK1 Inhibitors for Tumor Regression and Apoptosis in Hematologic and Solid Tumor Models

Two newly discovered PDK1 kinase inhibitors, SNS-229 and SNS-510, have been found to effectively block both PI-dependent and PI-independent substrate phosphorylation, demonstrating significant anti-tumor effects in various hematologic cancers. These inhibitors bind to the inactive state of PDK1, as revealed by X-ray crystallography, and their binding in the adaptive pocket alters the N-terminal domain and PIF-pocket, impacting PI-independent substrate binding.
SNS-510 was tested across more than 20 hematologic cancer cell lines, showing potent anti-proliferative capabilities with EC50 values ranging from 3 nM to 900 nM. Notably, it exhibited particularly strong effects in AML, DLBCL, and MM cell lines. The anti-proliferative activity was linked to the inhibition of PDK1, RSK, and AKT phosphorylation, with a time-dependent increase in PDK1 inhibition observed over 24 hours. SNS-510 also induced substantial apoptosis and was found to be significantly more potent than the PDK1 inhibitor GSK2334470 in inhibiting PDK1 and RSK phosphorylation and in cell viability assays. In vivo studies in mice confirmed good oral bioavailability and prolonged exposure for both SNS-229 and SNS-510. In a MV4-11 xenograft mouse model, dose-dependent pathway modulation was observed following a single oral dose, and after 21 days of dosing, both inhibitors showed significant tumor growth inhibition and partial regression. These findings suggest that targeting the inactive conformation of PDK1 to inhibit PI-independent substrate binding may offer a broad therapeutic potential for treating both solid and hematologic cancers.