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SNS-510: A Selective Oral PDK1 Inhibitor

We are also developing a potential first-in class, preclinical inhibitor of the novel target PDK1. In January 2014, we in-licensed a series of selective oral 3-phosphoinositide dependent protein kinase 1 (PDK1) inhibitors from Millennium that were discovered under a research collaboration agreement between Biogen Idec and Sunesis. PDK1 is critical for activation of the PI3K/AKT signaling pathway, which is essential for regulating cell growth, differentiation, survival and migration and is therefore frequently activated in cancer. We have advanced SNS-510 into IND-enabling development with the goal of filing an IND in 2019.

PDK1 is a master kinase that activates many key protein kinases (including AKT, PKC, and S6 among others). PDK1 directly phosphorylates AKT and represents an important potential anticancer target of a range of malignancies. .

Increasing evidence supports the importance of PDK1 in tumor growth and progression. Positioned at the crossroad of PI3K/AKT pathways, PDK1 is a very promising target for cancer treatment and may also provide additional benefits with its role in the tumor microenvironment. PDK1 inhibition may also have the potential to restore sensitivity to PI3K inhibitors, activating a different signaling pathway thereby bypassing PI3K inhibition.

There is a broad range of potential therapeutic targets in both hematology and solid tumor settings where the PI3K/AKT/mTOR pathway is activated including CLL, CML, AML, APL, T-ALL, prostate, colorectal, and ovarian cancers. The PDK1 pathway is one of the most frequently deregulated in human cancer. Increased expression of PDK1 is associated with advanced tumor stage and lower overall survival.

Further, PDK1 inhibition may have synergistic effects with many drugs, in many settings, counteracting invasion, metastasis and chemoresistance, with increasing evidence for the role of PDK1 in chemoresistance. Targeting PDK1 for chemosensitization of cancer cells and targeting PDK1 to act on resistant targets are two important potential applications for PDK1 inhibitors. Because PDK1-dependent activation of AKT is critical for PI3K pathway activation, we believe that PDK1 represents a key oncology target within the PI3K pathway. We believe Sunesis' PDK1 inhibitors are potential first-in-class compounds with demonstrated inhibition of AKT activity and a compelling in vitro and in vivo profile, that have potential for single agent and broad-spectrum combination activity, thus providing a novel therapeutic opportunity for targeting the PI3K signaling pathway in both solid and hematologic malignancies.

Presentations

Download presentations members of our team have given at recent conferences and meetings.
SNS-510 (PDK1) Program Presentations