For research use only. Not for therapeutic Use.
PHT-427（Cat No.:I000696）is a small-molecule inhibitor that targets both Akt and phosphoinositide-dependent kinase-1 (PDK-1), key components of the PI3K/Akt signaling pathway involved in cancer cell survival, growth, and resistance to apoptosis. By disrupting the interaction between PDK-1 and Akt, PHT-427 effectively blocks downstream signaling, reducing tumor cell proliferation and promoting cell death. It has shown promise in preclinical studies for treating various cancers, including pancreatic, breast, and lung cancers. PHT-427’s dual-target inhibition offers potential for overcoming resistance to therapies targeting individual components of this pathway.
| Catalog Number | I000696 |
| CAS Number | 1191951-57-1 |
| Synonyms | 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide |
| Molecular Formula | C₂₀H₃₁N₃O₃S₂ |
| Purity | ≥95% |
| Target | Akt |
| Solubility | DMSO ≥80mg/mL Water ≥4.6mg/mL Ethanol ≥80mg/mL |
| Storage | 3 years -20C powder |
| IC50 | 2.7/5.2 uM (Ki, Akt/PDPK1) |
| IUPAC Name | 4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide |
| InChI | InChI=1S/C20H31N3O2S2/c1-2-3-4-5-6-7-8-9-10-11-12-18-13-15-19(16-14-18)27(24,25)23-20-22-21-17-26-20/h13-17H,2-12H2,1H3,(H,22,23) |
| InChIKey | BYWWNRBKPCPJMG-UHFFFAOYSA-N |
| SMILES | CCCCCCCCCCCCC1=CC=C(C=C1)S(=O)(=O)NC2=NN=CS2 |
| Reference | 1:Mol Cancer Ther. 2010 Mar;9(3):706-17. doi: 10.1158/1535-7163.MCT-09-0985. Epub 2010 Mar 2. Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.Meuillet EJ,Zuohe S,Lemos R,Ihle N,Kingston J,Watkins R,Moses SA,Zhang S,Du-Cuny L,Herbst R,Jacoby JJ,Zhou LL,Ahad AM,Mash EA,Kirkpatrick DL,Powis G, PMID: 20197390 PMCID: PMC2837366 DOI: 10.1158/1535-7163.MCT-09-0985 </br><span>Abstract:</span> 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 and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1. A series of PHT-427 analogues with variable C-4 to C-16 alkyl chain length were synthesized and tested. PHT-427 itself (C-12 chain) bound with the highest affinity to the PH domains of both PDPK1 and Akt. PHT-427 inhibited Akt and PDPK1 signaling and their downstream targets in sensitive but not resistant cells and tumor xenografts. When given orally, PHT-427 inhibited the growth of human tumor xenografts in immunodeficient mice, with up to 80% inhibition in the most sensitive tumors, and showed greater activity than analogues with C4, C6, or C8 alkyl chains. Inhibition of PDPK1 was more closely correlated to antitumor activity than Akt inhibition. Tumors with PIK3CA mutation were the most sensitive, and K-Ras mutant tumors were the least sensitive. Combination studies showed that PHT-427 has greater than additive antitumor activity with paclitaxel in breast cancer and with erlotinib in non-small cell lung cancer. When given >5 days, PHT-427 caused no weight loss or change in blood chemistry. Thus, we report a novel PH domain binding inhibitor of PDPK1/Akt signaling with significant in vivo antitumor activity and minimal toxicity. |
