Abstract C198: PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors

Background and purpose: Phosphatidyl-inositol (PI) dependent kinase 1, PDK1, is a master kinase that activates kinases important in cell growth and survival including members of the AKT, PKC, RSK and SGK families. PDK1 can interact with its substrates through PI-dependent (PH-mediated) or PI-independent (PIF-mediated) mechanisms. Here we report characterization of two potent PDK1 kinase inhibitors, SNS-229 and SNS-510, that block both PI-dependent and PI-independent substrate phosphorylation and have broad anti-tumor activity in hematologic cancers. Methods and results: SNS-229 and SNS-510 belong to a series of novel PDK1 inhibitors that bind the inactive conformation of PDK1 as determined by X-ray crystallography. The compounds bind deep in the adaptive pocket, distorting the N-terminal domain and perturbing the PIF-pocket, thereby affecting PI-independent substrate binding. SNS-510 was evaluated in more than 20 cell lines derived from hematologic cancers including AML, MM, DLBCL, and MCL and showed strong anti-proliferative activity with EC50s ranging from 3 nM to 900 nM, with particularly strong activity observed in the AML cell lines Molm-13 and MV4-11 (EC50 3 and 7 nM), the DLBCL cell line U-2932 (EC50 56 nM) and the MM cell lines U-266 and RPMI-8226 (EC50 130 and 163 nM). Anti-proliferative activity correlated with pathway modulation as assessed by inhibition of phosphorylation of PDK1, RSK, and AKT. Interestingly, inhibition of PDK1 phosphorylation was time-dependent showing 2 to 5-fold more inhibition after 24 hours than at 4 hours. In addition, SNS-510 produced substantial apoptosis after 24 hours. SNS-510 was compared to the PDK1 inhibitor GSK2334470, showing comparable biochemical potency. However, SNS-510 was 10 to 30 fold more potent at inhibiting PDK1 and RSK phosphorylation in all cell lines tested. SNS-510 was at least 10-fold more potent than GSK2334470 in 72 hour viability assays. In mice, SNS-229 and SNS-510 showed good oral bioavailability (%F>40%) with a Tmax of 4 to 8 hours and prolonged exposure. Pathway modulation was evaluated in vivo in a MV4-11 xenograft mouse model. Potent, dose-dependent pathway modulation was observed at 4 and 24 hours after a single oral dose of SNS-229 and SNS-510 (1 to 25 mg/kg). After 21- day dosing in MV4-11 xenografts, both SNS-229 and SNS-510 showed dose-related efficacy with > 95% tumor growth inhibition and partial regression (>50% tumor shrinkage) in 70% and 100% of animals at the highest dose. Conclusion: With this class of PDK1 inhibitors, we have previously reported strong tumor growth inhibition (66%-95%) in gastric, lung, pancreatic and colorectal cancer xenograft models. Here we report a PK/PD (pathway modulation) relationship that correlates with profound tumor growth inhibition in hematologic cancers. Thus, targeting the inactive conformation of PDK1 and inhibiting PI-independent substrate binding has broad potential for the treatment of solid and hematologic cancers. Citation Format: Stig Hansen, Johan Enquist, Jeff Iwig, Minke E. Binnerts, Gene Jamieson, Judith A. Fox, Adam R. Craig. PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C198.