Abstract 4413: Mechanisms of sensitivity to treatment with the PDK1 inhibitors HCI-1680 and HCI-1708.
Authors: Walker Brian , Venkataswamy Sorna , Warner Steven , Call Lee , Vankayalapati Hariprasad , Sharma Sunil , Bearss David J. 
Published: August 2014

The phosphoinositide-dependent kinase-1 (PDK1) is a serine/threonine kinase that has been considered a promising potential oncology drug target because of its role as an important regulator in the PI3K/AKT/mTOR pathway. PDK1 phosphorylates highly conserved Ser or Thr residues in the activation loop of several AGC super family kinases including PKC, SGK, PKB/Akt, p70S6K, and PDK1 itself. Approximately, 40-50% of all tumors involve mutations in the phosphatase and tensin homolog (PTEN) protein, which results in elevated levels of PIP3 and enhanced activation of PKB/AKT, p70S6K, and SGK. It has been proposed that inhibitors of PDK1 could provide a valuable therapeutic approach to targeting cancer, particularly those with PTEN deficiencies. Using a fragment-based design strategy, we screened a collection of 1100 low molecular weight (&lt; 250 MW) fragments against the PDK1 kinase and identified 9 fragments with moderate inhibitory activity against PDK1 (IC50 values from 45-82 μM). Subsequent molecular docking studies using a crystal structure of PDK1 allowed for the structural rationalization of how these fragments bound in the ATP-binding pocket (hydrogen bonding to S160/A162 hinge residues) and provided insight for further optimization. Synthesis and follow-up screening led to the discovery of HCI-1680 and a related compound SGI-1708, as potent PDK1 inhibitors with IC50 values of 80 and 94 nM, respectively. We used a large cell line panel of over 100 cancer cell lines to examine the ability of these compounds to kill cancer cells. Both HCI-1680 and SGI-1708 demonstrated remarkable selectivity for cell killing in several cell lines (KATO3, KG-1, MV4-11, Kasumi-1, MFE296 and AN3CA) in the low nanomolar range compared to all of the remaining cell lines in which the compounds showed low micromolar activity. Based on the known mutations in these cell lines we determined that HCI-1680 and SGI-1708 were more active in cells with PTEN deletion/silencing as well as activation of PIK3CA through activating mutations in PIK3CA or Ras proteins. Our compounds from this series were also shown to inhibit the activation of AKT and other downstream signaling molecules. We have explored the effects on gene expression Moreover, the lead compounds had high ligand efficiency with promising solubility and permeability parameters. Early animal studies examining pharmacokinetics and efficacy in xenograft models of human cancers have suggested that HCI-1680 and SGI-1708 have properties and activity to be developed as potential clinical candidates. We hypothesize that tumors, which have inactivated PTEN through mutations or silencing and also harbor mutations that activate PI3K define a population of cancer cells that are uniquely sensitive to PDK1 Inhibition. By inhibiting PDK1 activity we will block signaling from the PI3K pathway and lead to inhibition of cell proliferation and survival of these cancer cells.

Citation Format: Brian Walker, Sorna Venkataswamy, Steven Warner, Lee Call, Hariprasad Vankayalapati, Sunil Sharma, David J. Bearss. Mechanisms of sensitivity to treatment with the PDK1 inhibitors HCI-1680 and HCI-1708. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4413. doi:10.1158/1538-7445.AM2013-4413