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.
- PHT-427 locates in the cytosol and through its inhibition of PDK1 prevents PDK1 from activating Akt and other downstream effectors such a p-S6-Ser240 and p-GSK?-Ser9.
- Inhibition of PDK1 correlates to the peak plasma concentration of PHT-427 in animals.
- Anti-tumor activity has been observed in a number of human tumor xenografts, some with complete cessation of tumor growth during administration. Tumor regressions havs also been observed.
- PHT-427 in combination with chemotherapy proves effective in non-small-cell lung cancer, a significant market, where despite treatment advances there is a 5 year survival of only 15%.
- PHT-427 shows excellent antitumor activity against melanoma PDX tumors with NRAS mutations that are resistant to BRAF inhibitors.
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- PHT-427 has entered IND enable studies, demonstrating a good safety profile for both oral and topical drug products.
- Pre-clinical development continues with a Phase 1 clinical trial planned.
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.
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