PHusis Therapeutics Technology

PDK1 inhibitor: PHT – 427

In a study to identify novel PDK1 PH-domain inhibitors, PHusis’ iterative screening process identified an inhibitor of PDK1, the novel small molecule PHT-427 that has shown oral antitumor activity and has efficacy with topical application against skin cancers and cutaneous tumors. It works by blocking the PI3-kinase/mTOR signaling pathway that drives lung cancer, melanoma and skin cancers as well as the aggressive inflammatory breast cancer (IBC). PDK1, acts in part through FOXO3a-dependent pathway, , and has been shown to be important in melanoma development and progression.* Inhibition of PDK1 has been reported to reverse the resistance to BRAF inhibitors in melanoma models causing regressing of established tumors**. PHT-427 has recently been shown to be effective in melanoma models in vivo and is being further explored for its ability to overcome mutant BRAF inhibitor resistance in these models.

*  Oncogene2014;33(34):4330-9. ) Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of Braf(V600E)::Pten(-/-) melanoma. 1–10. doi:10.1038/onc.2013.383.
** Nature 498: 109, 2013.

PDPK1 inhibitor: PHT – 427

Overlay of the best docked pose of PHT- 427 (cyan sticks) and the co-crystallized IP4 (green sticks) from the high resolution structure of the pleckstrin homology domain.