Molecular pharmacology and antitumor activity of PHT-427, a novel akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor

Molecular Cancer Therapeutics

Volumn 9, Issue 3, 2010, Pages 706-717

  Meuillet, Emmanuelle J ^a   Zuohe, Song ^a   Lemos, Robert ^c   Ihle, Nathan ^c   Kingston, John ^c   Watkins, Ryan ^c   Moses, Sylvestor A ^a   Zhang, Shuxing ^c   Du Cuny, Lei ^c   Herbst, Roy ^c   Jacoby, Jörg J ^c   Zhou, Li Li ^b   Ahad, Ali M ^b   Mash, Eugene A ^b   Kirkpatrick, D Lynn ^d   Powis, Garth ^c  

^a UNIVERSITY OF ARIZONA   (United States)

^b University of Arizona   (United States)

^c UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^d PHusis Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ERLOTINIB; PACLITAXEL; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHT 427; PLECKSTRIN; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BINDING AFFINITY; BLOOD CHEMISTRY; BREAST CANCER; CANCER INHIBITION; CONTROLLED STUDY; DRUG BINDING; DRUG INHIBITION; DRUG SENSITIVITY; ENZYME INHIBITION; FEMALE; GENE MUTATION; HUMAN; HUMAN CELL; IMMUNE DEFICIENCY; IN VIVO STUDY; LUNG NON SMALL CELL CANCER; MOUSE; NONHUMAN; ONCOGENE K RAS; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; TREATMENT DURATION; TUMOR XENOGRAFT; WEIGHT REDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; FEMALE; HUMANS; MICE; MICE, INBRED C57BL; MICE, NUDE; MODELS, BIOLOGICAL; ONCOGENE PROTEIN V-AKT; PROTEIN BINDING; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTEIN KINASE INHIBITORS; PROTEIN-SERINE-THREONINE KINASES; SULFONAMIDES; THIADIAZOLES; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 77949681661     PISSN: 15357163     EISSN: None     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-09-0985     Document Type: Article

References (43)

1. Rebecchi MJ, Scarlata S. Pleckstrin homology domains: a common fold with diverse functions. Annu Rev Biophys Biomol Struct 1998; 27:503-28.
2. Workman P, Clarke PA, Guillard S, Raynaud FI. Drugging the PI3 kinome. Nat Biotechnol 2006;24:794-6.
3. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002;14:381-95.
4. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 1999;96:4240-5.
5. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008;27:5486-96.
6. Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett 2003;546:108-12.
7. Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr Biol 1997;7:261-9.
8. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-101.
9. Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 1998;273:32377-9.
10. S6k activation mediated by phosphatidy- linositol-3-OH kinase. Nature 1994;370:71-5.
11. van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J, Burgering BM. Essential role for protein kinase B (PKB) in insulininduced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem 1998;273:13150-6.
12. Zhong H, Chiles K, Feldser D, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res 2000;60:1541-5.
13. Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 2004;22:2954-63.
14. Carptener JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448: 439-44.
15. Li Q. Recent progress in the discovery of Akt inhibitors as anticancer agents. Expert Opin Ther Patents 2007;17:1077-130.
16. Alessi D. Discovery of PDK1, one of the missing links in insulin signal transduction. Biochem Soc Trans 2001;29:1-14.
17. Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDPK1 is essential for activation of S6K and SGK, but not PKB. EMBO 2001;20:4380-90.
18. Casamayor A, Morrice NA, Alessi DR. Phosphorylation of ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 1999;342:287-92.
19. Avruch J, Belham C, Weng Q, Hara K, Yonezawa K. The p70 S6 kinase integrates nutrient and growth signals to control translational capacity. Prog Mol Subcell Biol 2001;26:115-54.
20. Frodin M, Gammeltoft S. Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol 1999;151: 65-77.
21. Dutil EM, Toker A, Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1(PDK-1). Curr Biol 1998;8:1366-75.
22. Kobayashi T, Cohen P. Activation of serum- and glucocorticoidregulated protein kinase by agonists that activate phosphatidylinositide-3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDPK1) and PDK2. Biochem J 1999;339:319-28.
23. Maurer M, Su T, Saal LH, et al. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 2009;69: 6299-306.
24. Vasudevan KM, Barbie DA, Davies MA, et al. PDK1-SGK3 signaling in the absence of AKT activation in PIK3CA-mutant cancers. Cancer Cell 2009;16:21-32.
25. Mahadevan D, Powis G, Mash EA, et al. Discovery of a novel class of AKT pleckstrin homology domain inhibitors. Mol Cancer Ther 2008;7: 2621-32.
26. Moses SA, Ali A, Zuohe S, et al. Cancer Res 2009;69:5073-81.
27. Du-Cuny L, Song Z, Moses S, et al. Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain. Bioorg Med Chem 2009;17:6983-92.
28. Hu J, He X, Baggerly KA, Coombes KR, Hennessy BT, Mills GB. Non-parametric quantification of protein lysate arrays. Bioinformatics 2007;23:1986-94.
29. Paine GD, Taylor CW, Curtis RA, et al. Human tumor models in the severe combined immune deficient scid mouse. Cancer Chemother Pharmacol 1997;40:209-14.
30. Onn A, Isobe T, Itasaka S, Wu W, O'Reilly MS. Development of an orthotopic model to study the biology and therapy of primary human lung cancer in nude mice. Clin Can Res 2003;9:5532-9.
31. Meuillet EJ, Mahadevan D, Vankayalapati H. Specific inhibition of the Akt1 pleckstrin homology domain by D-3-deoxy-phosphatidylmyo-inositol analogues. Cancer Res 2003;2:389-99.
32. 2 [abstract 645]. Proc Am Assoc Cancer Res Annu Meet 2007.
33. Ruiter GA, Zerp SF, Bartelink H, et al. Anti-cancer alkyl- lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs 2003;14:167-73.
34. Kim D, Cheng GZ, Lindsley CW, Yang H, Cheng JQ. Targeting the phosphatidylinositol-3 kinase/Akt pathway for the treatment of cancer. Curr Opin Investig Drugs 2005;6:1250-8.
35. Lu W, Defeo-Jones D, Davis L, et al. In vitro and in vivo antitumor activities of MK-2206, a new allosteric AKT inhibitor. Proc Am Assoc Cancer Res Annu Meet 2009;2009:3714.
36. Sonnenburg ED, Gao T, Newton AC. The phosphoinositide-dependent kinase, PDK-1, phosphorylates conventional protein kinase C isozymes by a mechanism that is independent of phosphoinositide 3-kinase. J Biol Chem 2001;276:45289-97.
37. Carlisle J, Townley I, Dodge-Kafka K, et al. Spatial restriction of PDK1 activation cascades by anchoring to mAKAPα. Mol Cell 2005;20:661-72.
38. Ihle NT, Lemos R, Wipf P. Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 2009;69:143-8.
39. Meuillet EJ, Ihle N, Baker AF, et al. In vivo molecular pharmacology and antitumor activity of the targeted Akt inhibitor PX-316. Oncol Res 2004;14:513-27.
40. Hennessy B, Lu Y, Poradosu E, et al. Pharmacodynamic markers of perifosine efficacy. Clin Cancer Res 2007;13:7421-31.
41. Huang BX, Kim H-Y. Probing Akt-inhibitor interaction by chemical cross-linking and mass spectrometry. J Am Soc Mass Spectrom 2009;20:1504-13.
42. Calleja V, Laguerre M, Parker PJ, Larijani B. Role of a novel PH-kinase domain interface in PKB/Akt regulation: structural mechanism for allosteric inhibition. PLoS Biol 2009;7:189-200.
43. Kang S, Denley A, Vanhaesebroeck B, Vogt PK. Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci U S A 2006;103:1289-94.