PHT-427

• CAT Number: I000696
• CAS Number: 1191951-57-1
• Molecular Formula: C₂₀H₃₁N₃O₃S₂
• Molecular Weight: 409.61
• 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) [1]
• 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

PHT-427 is a dual Akt and PDPK1 inhibitor (high affinity binding for the PH domains of Akt and PDPK1) with Ki of 2.7 μM and 5.2 μM, respectively.IC50 value: 2.7/5.2 uM (Ki, Akt/PDPK1) [1]Target: Akt/PDPK1in vitro: PH-427 is a pleckstrin homology domain inhibitor to Akt/PDPK1. PH-427 significantly reduces phospho-Ser241-PDPK1 phospho-Thr308-Akt in PC-3 prostate cancer cells at 10 μM, which shows that PHT-427 could inhibit both Akt and PDKP1. PHT-427 also inhibits translocation of the Akt and PDKP1 PH domains in plasma membrane [1]. PHT-427 induces apoptosis and inhibits AKT phosphorylation with IC50 of 8.6 μM (in BxPC-3 cells), which mainly on its Ser473 residue and less strongly on Thr308 residue without affecting total Akt protein expression. PHT-427 also shows antiproliferation in Panc-1 cells with IC50 of 65 μM [2].in vivo: PHT-427 shows great antitumor activity in BxPC-3 pancreatic, MCF-7 breast and A-549 NSCL cancer xenografts. PHT-427 gives up to an 80% inhibition of tumor growth in BxPC-3 at doses of 125 to 250 mg/kg [1].

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 Abstract: 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.