Molecular Pharmacology and Antitumor Activity of PHT-427, a Novel Akt/Phosphatidylinositide-Dependent Protein Kinase 1 Pleckstrin Homology Domain Inhibitor

摘要: Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology antitumor activity of PHT-427, compound designed to bind pleckstrin homology (PH) binding domain molecules important cancer. Although originally PH Akt, we now that PHT-427 also binds PDPK1. A series analogues with variable C-4 C-16 alkyl chain length were synthesized tested. itself (C-12 chain) bound highest affinity domains both PDPK1 Akt. inhibited Akt their downstream targets sensitive but not resistant cells tumor xenografts. When given orally, growth human xenografts immunodeficient mice, up 80% inhibition most tumors, showed greater than C4, C6, or C8 chains. Inhibition was more closely correlated inhibition. Tumors PIK3CA mutation sensitive, K-Ras mutant tumors least sensitive. Combination studies has additive paclitaxel breast erlotinib non-small cell lung >5 days, caused no weight loss change blood chemistry. Thus, novel inhibitor PDPK1/Akt significant vivo minimal toxicity.