From the bench to the bed side: PI3K pathway inhibitors in clinical development

Current Topics in Microbiology and Immunology

Volumn 347, Issue 1, 2010, Pages 209-239

  Maira, Saveur Michel ^a   Finan, Peter ^b   Garcia Echeverria, Carlos ^a  

^a Oncology Drug Discovery   (France)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (2 DIFLUOROMETHYLBENZIMIDAZOL 1 YL) 4,6 DIMORPHOLINO 1,3,5 TRIAZINE; 2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; 2 (6 AMINO 9 PURINYLMETHYL) 5 METHYL 3 (2 METHYLPHENYL) 3H QUINAZOLIN 4 ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; 5 (6 QUINOXALINYLMETHYLENE) 2,4 THIAZOLIDINEDIONE; 5 FLUORO 3 PHENYL 2 [1 (9H PURIN 6 YLAMINO)PROPYL] 3H QUINAZOLIN 4 ONE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; AEZS 126; ANTINEOPLASTIC AGENT; CA 125 ANTIGEN; D 106669; ERLOTINIB; GSK 1059615; HEAT SHOCK PROTEIN 90; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; NVP BGT 226; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PICTRELISIB; PROTEIN KINASE B; RAPAMYCIN; TRASTUZUMAB; UCB 1320437; UNCLASSIFIED DRUG; UNINDEXED DRUG; WORTMANNIN; XL 147; XL 765; ISOENZYME; PROTEIN KINASE INHIBITOR;

ABSENCE OF SIDE EFFECTS; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALLERGY; ANOREXIA; ANTINEOPLASTIC ACTIVITY; ARTERY THROMBOSIS; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHMA; ATHEROSCLEROSIS; B CELL LYMPHOMA; BREAST CANCER; CANCER CELL; CANCER CELL CULTURE; CELL ACTIVATION; CELL PROLIFERATION; CHRONIC LYMPHATIC LEUKEMIA; CONTINUOUS INFUSION; DOSAGE SCHEDULE COMPARISON; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG ERUPTION; DRUG HALF LIFE; DRUG POTENTIATION; DRUG SPECIFICITY; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; HEADACHE; HEMATOLOGIC MALIGNANCY; HUMAN; HYPERGLYCEMIA; HYPOPHOSPHATEMIA; INHIBITION KINETICS; LUNG NON SMALL CELL CANCER; LYMPHOMA; MALIGNANT NEOPLASTIC DISEASE; MAST CELL; MAXIMUM PLASMA CONCENTRATION; MELANOMA; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; NAUSEA AND VOMITING; NONHODGKIN LYMPHOMA; NONHUMAN; OVARY CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PLEURA EFFUSION; PRIORITY JOURNAL; PROSTATE CANCER; RHEUMATOID ARTHRITIS; SIDE EFFECT; SYSTEMIC LUPUS ERYTHEMATOSUS; ANIMAL; ARTHRITIS; DRUG ANTAGONISM; DRUG DEVELOPMENT; DRUG EFFECT; LUNG DISEASE; NEOPLASM; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; ARTHRITIS; DRUG DISCOVERY; HSP90 HEAT-SHOCK PROTEINS; HUMANS; ISOENZYMES; LUNG DISEASES; LUPUS ERYTHEMATOSUS, SYSTEMIC; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 79952109693     PISSN: 0070217X     EISSN: None     Source Type: Book Series    
DOI: 10.1007/82-2010-60     Document Type: Article

References (136)

1. Abraham RT, Eng CH (2008) Mammalian target of rapamycin as a therapeutic target in oncology. Expert Opin Ther Targets 12:209-222 (Pubitemid 351284963)
2. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B (2004) Essential role for the p110d phosphoinositide 3-kinase in the allergic response. Nature 431:1007-1011 (Pubitemid 39434424)
3. Ali K, Camps M, Pearce WP, Ji H, Ruckle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B (2008) Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 180:2538-2544
4. Amzel LM, Huang CH, Mandelker D, Lengauer C, Gabelli SB, Vogelstein B (2008) Structural comparisons of class I phosphoinositide 3-kinases. Nat Rev Cancer 8:665-669
5. Auger KR, Luo L, Knight S, Van Aller G, Tummino PJ, Copeland RA, Diamond M, Sutton D, Jackson JR, Dhanak D (2008) A novel inhibitor of phosphoinositide 3-kinase for the treatment of cancer (poster). Presented at 20th EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics, Geneva, Switzerland, 21-24 October 2008
6. Bachman KE (2008) GSK615: A novel inhibitor of phosphoinositide 3-kinase for the treatment of cancer. Presented at AACR special conference in cancer research -Targeting the PI3-Kinase pathway in cancer, Cambridge, USA, 11-14 November 2008
7. Barber DF, Bartolome A, Hernandez C, Flores JM, Redondo C, Fernandez-Arias C, Camps M, Ruckle T, Schwarz MK, Rodriguez S, Martinez A, Balomenos D, Rommel C, Carrera AC (2005) PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med 11:933-935 (Pubitemid 41294437)
8. Barnett SF, Defeo-Jones D, Fu S, Hancok PJ, Haskell K, Jones RE, Kahana JA, Kral AM, Leander K, Lee LL, Malinowski J, McAvoy EM, Nahas DD, Robinson RG, Huber HE (2005) Identification and characterization of pleckstrin homology domain dependent and isozyme specific Akt inhibitors. Biochem J 385:399-408
9. Basso AD, Solit DB, Munster PN, Rosen N (2002) Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpresses HER2. Oncogene 21:1159-1166 (Pubitemid 34185232)
10. Baumann P, Mandl-Weber S, Oduncu F, Schmidmaier R (2009) The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res 315:485-497
11. Bhagwat SV, Crew AP, Gokhale PC, Cooke A, Kahler J, Yao Y, Chan A, Arnold LD, Wild R, Pachter JA (2008) Cellular characterization of OXA-0, a potent and selective dual mTORC1 and mTORC2 kinase inhibitor. Presented at 20th EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics, Geneva, Switzerland, 21-24 October 2008
12. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL (1999) Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 274:10963-10968
13. Bi L, Okabe I, Bernard DJ, Nussbaum RL (2002) Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mamm Genome 13:169-172 (Pubitemid 34185317)
14. Bishop SC, Burlison JA, Blagg BSJ (2007) Hsp90: a novel target for the disruption of multiple signaling cascades. Curr Med Chem 7:369-388 (Pubitemid 46849241)
15. Brough PS, Aherne W, Barril X et al (2008) 4, 5-Diaryl-isoxazole hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51:196-218
16. Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C et al (2005a) Blockade of PI3Kg suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936-943 (Pubitemid 41294438)
17. Camps M, Rückle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B,Martin T, Gretener D, Perrin D, Leroy D, Vitte PA, Hirsch E,Wymann MP, Cirillo R, Schwarz MK, Rommel C (2005b) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nat Med 11:936-943 (Pubitemid 41294438)
18. Cao P, Maira SM, Garcia-Echeverria C, Hedley DW (2009) Activity of a novel, dual PI3-kinase/ mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts. Br J Cancer 100:1267-1276
19. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S et al (2007) A transforming mutation in the pleckstrin homology domain of Akt1 in cancer. Nature 448:439-444 (Pubitemid 47123510)
20. Chandarlapaty S, Sawai A, Ye Q, Scott A, Silinski M, Huang K, Fadden P, Partdrige J, Hall S, Steed P, Norton L, Rosen N, Solit DB (2008) SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 14:240-248 (Pubitemid 351378001)
21. Chiorean EG, Mahadevan D, Harris WB, Von Hoff DD, Younger AE, Rensvold DM, Shelton CF, Hennessy BT, Garlich JR, Ramanathan RK (2009) Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly IV in patients with refractory solid tumors. J Clin Oncol (Meeting Abstracts) 27:2558
22. Chiosis G, Huezo H, Rosen N, Mimnaugh E, Whitesell L, Neckers L (2003) 17AAG: Low Target Binding Affinity and Potent Cell ActivityGÇ öFinding an Explanation1. Mol Cancer Ther 2:123-129
23. Chresta CM, Davies BR, Harding T, Hickson I, Cosulich S, Crichtlow S, Sini P, James D, Malagu K, Hummersone M, Smith GCM, Pass M, Guichard M (2009) Characterization of AZD8055, a potent selective inhibitor of mTORC1 and mTORC2 kinase (poster). Presented at 100th AACR annual meeting, Denver, USA, 18-22 April 2009
24. Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C, Wu H, Dastru W, Martin EL, Silengo L, Altruda F, Turco E, Lanzetti L, Musiani P, Ruckle T, Rommel C, Backer JM, Forni G, Wymann MP, Hirsch E (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 1:ra3
25. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA Jr., Watson MA, Saporita A, Weber JD, Ellis MJ (2009) PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 69:3955-3962
26. Dasmahapatra GP, Didolkar P, Alley MC, Ghosh S, Sausville EA, Roy KK (2004) In vitro combination treatment with perifosine and UCN-01 demonstrates synergism against prostate (PC-3) and lung (A549) epithelial adenocarcinoma cell lines. Clin Cancer Res 10:5242-5252 (Pubitemid 39099799)
27. Davies TD, Verdonk ML, Graham B, Saalau-Bethell S, Hamlett CCF, McHardy T, Collins I, Garrett MD, Workman P, Woodhead SJ, Jhoti H, Barford D (2007) A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol 367:882-894 (Pubitemid 46335912)
28. Davies BR, Chresta CM, Dudley P, Hewitt N, Brady M, Jacobsen M, Hickson I, Martin NMB, Smith GCM, Pass M (2008) Pharmacodynamics and anti-tumor activity of KU-0063794, a potent and specific inhibitor of mTOR kinase. Presented at 20th EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics, Geneva, Switzerland, 21-24 October 2008
29. Domin J, Waterfield MD (1997) Using structure to define the function of phosphoinositide 3-kinase family members. FEBS Lett 410:91-95 (Pubitemid 27283391)
30. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C, Schultz PG, Reddy VA (2009) The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 106:268-273
31. Eccles S, Massey A, Raynaud FI, Sharp SY, Bax G, Valenti M, Patterson L, Ad B, Gowan S, Boxall F, Aherne W, Rowlands M et al (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68:2850-2860 (Pubitemid 351556284)
32. Egorin MJ, Parise RA, Joseph E, Hamburger DR, Lan J, Covey JM, Eiseman JL (2002) Plasma pharmacokinetics and bioavailability of the phosphatidylinositide-3-kinase signalling inhibitor, OMDPI (NSC 710297), in CD2F1 mice. Proc Am Assoc Cancer Res 43:abstract 2996
33. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221-9230
34. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-1356
35. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Activesite inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38
36. Flinn IW, Byrd JC, Furman RR, Brown JR, Lin TS, Bello C, Giese NA, Yu AS (2009) Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p1108 isoform of phosphatidylinositol 3-kinase (P13K), in patients with select hematologic malignancies. J Clin Oncol (Meeting Abstracts) 27:3543
37. Folkes A, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A et al (2008) The identification of 2-(1Hindazol-4-yl)-6-(4-methanesulfonyl-1-piperazin-1- ylmethyl)-4-morpholin-4-yl-thieno[3,2-d] pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 Kinase for the treatment of cancer. J Med Chem 51:5522-5532
38. Fougerat A, Gayral S, Gourdy P, Schambourg A, Ruckle T, Schwarz MK, Rommel C, Hirsch E, Arnal JF, Salles JP, Perret B, Breton-Douillon M, Wymann MP, Laffargue M (2008) Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes. Circulation 117:1310-1317 (Pubitemid 351365672)
39. Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B (2006) Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441:366-370 (Pubitemid 44050203)
40. Friedman L (2008) Biomarkers of PI3K inhibitor GDC-0941. Presented at AACR special conference in cancer research -Targeting the PI3-Kinase pathway in cancer, Cambridge, USA, 11-14 November 2008
41. Fujita N, Sato S, Ishida A, Tsuruo T (2002) Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem 277:10346-10353 (Pubitemid 34968152)
42. Garlich JR, De P, Dey N, Su JD, Peng X, Miller A, Murali R, Lu Y, Mills GB, Kundra V, Shu HK, Peng Q, Durden DL (2008) A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 68:206-215 (Pubitemid 351380122)
43. Ge J, Normant E, Porter JR, Dembski MS, Gao Y, Georges AT, Grenier L et al (2008) Design, aynthesis, and biological evaluation of hydroquinone derivatives of 17-Amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 49:4606-4615
44. Giese NA (2008) Targeting PI3K p110 delta for the treatment of hematological malignancies. Presented at AACR special conference in cancer research -Targeting the PI3-Kinase pathway in cancer, Cambridge, USA, 11-14 November 2008
45. Greshock J (2008) In vitro sensitivity data identifies tumor types and molecular subtypes that predicts repsonse ton the PI3K inhibitor GSK1059615 and the Akt inhibitor GSK690693. Presented at AACR special conference in cancer research -Targeting the PI3-Kinase pathway in cancer, Cambridge, USA, 11-14 November 2008
46. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, Meek S, Smith AJ, Okkenhaug K, Vanhaesebroeck B (2008) The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci USA 105:8292-8297 (Pubitemid 351904749)
47. Han E-H, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, Giranda VL, Luo Y (2007) Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene 26:5655-5661 (Pubitemid 47267835)
48. Hartnett JC, Barnett SF, Bilodeau MT, Defeo-Jones D, Hartman GD, Huber HE, Jones RE, Kral AM, Robinson RG, Wu Z (2008) Optimization of 2,3,5-trisubstitued pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors. Bioorg Med Chem Lett 18:2194-2197 (Pubitemid 351380851)
49. Hawkins PT, Anderson KE, Davidson K, Stephens LR (2006) Signalling through Class I PI3Ks in mammalian cells. Biochem Soc Trans 34:647-662 (Pubitemid 44796393)
50. Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, Januario T, Savage H, Punnoose E, Truong T, Zhou W, Berry L, Murray L, Amler L, Belvin M, Friedman LS, Lackner MR (2009) In vivo Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast Cancer Models. Clin Cancer Res 15:4649-4664
51. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744-1748 (Pubitemid 350274378)
52. Huang CH, Mandelker D, Gabelli SB, Amzel LM (2008) Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell Cycle 7:1151-1156 (Pubitemid 351749265)
53. Huston A, Leleu X, Jia X, Moreau A-S, Ngo HT, Runnels J, Anderson J, Alsayed Y, Roccaro A, Vallet S et al (2008) Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment. Clin Cancer Res 14:865-874 (Pubitemid 351231171)
54. Ihle NT, Powis G (2009) Take your PIK: phosphatidylinositol 3-kinase inhibitors race through the clinic and toward cancer therapy. Mol Cancer Ther 8:1-9
55. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3:763-772 (Pubitemid 39193758)
56. Ihle NT, Paine-Murrieta G, BerggrenMI, Baker A, TateWR, Wipf P, Abraham RT, Kirkpatrick DL, Powis G (2005) The phosphatidylinositol-3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human non-small cell lung cancer xenografts. Mol Cancer Ther 4:1349-1357
57. Ihle NT, Lemos R, Schwartz D, Oh J, Halter RJ, Wipf P, Kirkpatrick L, Powis G (2009a) Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther 8:94-100
58. Ihle NT, Lemos R Jr., Wipf P, Yacoub A, Mitchell C, Siwak D, Mills GB, Dent P, Kirkpatrick DL, Powis G (2009b) 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 69:143-150
59. Janin YL (2005) Heat shock protein 90 inhibitors. A text book example of medicinal chemistry? J Med Chem 48:7503-7512 (Pubitemid 41698792)
60. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A et al (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10:R33
61. Jia W, Yu C, Rahmani M, Krystal G, Sausville EA, Dent P, Grant S (2003) Synergistic antileukemic interactions between 17-AAG and UCN-01 involve interruption of RAF/MEK-and AKTrelated pathways. Blood 102:1824-1832 (Pubitemid 37022579)
62. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776-779
63. Jia S, Roberts TM, Zhao JJ (2009) Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199-208
64. Jimeno A, Hong DS, Hecker S, Clement R, Kurzrock R, Pestano LA, Hiscox A, Leos RA, Kirkpatrick DL, Eckhardt SG, Herbst RS (2009) Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor. J Clin Oncol (Meeting Abstracts) 27:3542
65. Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429-440
66. Kavorkian L, Watkins C, Jallal H, Payne A, Hutshinson G, Stubberfield C, Zinkewich-Peotti K (2008) Combination studies with a potent inhibiotr of PI3K, UCB1320437, and effects on cellular signalling and apoptosis (poster). Presented at AACR special conference in cancer research -Targeting the PI3-Kinase pathway in cancer, Cambridge, USA, 11-14 November 2008
67. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM (2006) Apharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733-747
68. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093-1103
69. Kong D, Yamori T (2007) ZSTK474 is an ATP-competitive inhibitor of class I phosphatidylinositol 3 kinase isoforms. Cancer Sci 98:1638-1642 (Pubitemid 47308463)
70. Kong D, Yaguchi S, Yamori T (2009) Effect of ZSTK474, a novel phosphatidylinositol 3-kinase inhibitor, on DNA-dependent protein kinase. Biol Pharm Bull 32:297-300
71. Kumar CC, Madison V (2001) Drugs targeted against protein kinases. Expert Opin Emerg Drugs 6 (2):303-315
72. Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E, Wymann MP (2002) Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity 16:441-451 (Pubitemid 34260921)
73. Lannuttti BJ, Meadows SA, Kashishian A, Steiner B, Chen H, Ulrich RG, Yu A, Puri KD, Giese NA (2009) CAL-101, a specific PI3K p110d inhibitor for the treatment of hematological malignancies (poster). Presented at 100th AACR annual meeting, Denver, USA, 18-22 April 2009
74. Li Q, Zhu GD (2002) Targeting serine/threonine protein kinase B/Akt and cell-cycle checkpoint kinases for treating cancer. Curr Top Med Chem 2:939-971
75. Li X, Luwor R, Lu Y, Liang K, Fan Z (2006) Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. Oncogene 25:525-535 (Pubitemid 43164463)
76. Lin T-Y, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C (2008) The novel Hsp90 inhibitor STA-9090 exhibits activity against Kit-dependen and -independent malignant mast cell tumors. Exp Hematol 36:1266-1277
77. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME (2005) Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15:761-764 (Pubitemid 40143162)
78. LoRusso P, Hurwitz H, Chiorean E, Jewell R, Lampkin T, Bachman K, Kumar R, Lebowitz P, Weber B (2008) AKT inhibitor GSK690693: Preliminary results from the first time in human study. AACR Meeting Abstracts 2008:LB-68
79. LoRusso P, Markman B, Tabernero J, Shazer R, Nguyen L, Heath E, Patnaik A, Papadopoulos K (2009) A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 27:3502
80. Lundgren K, Zhang H, Kamal A, Lough R, et al (2007) BIIB021 is a small molecule inhibitor of the heat shock protein, Hsp90, that shows potent anti-tumor activity in preclinical models. In: AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther
81. Lundgren K, Zhans H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang Y, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Ksibhatla SR, Boehm MF, Burrows FJ (2009) BII021, on orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Res 8:921-929
82. Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, Han EK, Li T, Stoll VS, Powlas JA, Oleksijew A, Mitten MJ, Shi Y et al (2005) Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Res 4:977-986 (Pubitemid 40909080)
83. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De PA, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C (2008a) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther 7:1851-1863
84. Maira SM, Voliva C, Garcia-Echeverria C (2008b) Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery. Expert Opin Ther Targets 12:223-238 (Pubitemid 351284964)
85. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594-601 (Pubitemid 38796850)
86. Marion F, Williams DE, Patrick BO, Hollander I, Mallon R, Kim SC, Roll DM, Feldberg L, Van SR, Andersen RJ (2006) Liphagal, a Selective inhibitor of PI3 kinase alpha isolated from the sponge akacoralliphaga: structure elucidation and biomimetic synthesis. Org Lett 8:321-324 (Pubitemid 43163992)
87. Marone R, Cmiljanovic V, Giese B, Wymann MP (2008) Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 1784:159-185
88. Marone R, Erhart D, Mertz AC, Bohnacker T, Schnell C, Cmiljanovic V, Stauffer F, Garcia-Echeverria C, Giese B, Maira SM, Wymann MP (2009) Targeting melanoma with dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors. Mol Cancer Res 7:601-613
89. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, Jakubikova J, Maira SM, Garcia-Echeverria C, Schlossman R, Munshi NC, Richardson PG, Anderson KC, Mitsiades CS (2009) Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/ mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res 69:5835-5842
90. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239-242 (Pubitemid 47076198)
91. Miller N (2008) mTORC1/mTORC2 selective inhibitors: Identification and characterization of novel small molecules with antitumor activity. Presented at 20th EORTC-NCI-AACR symposium on molecular targets and cancer therapeutics, Geneva, Switzerland, 21-24 October 2008
92. Modi S, Stopeck AT, Gordon MS, Mendelson D, Solit DB, Bagatell R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG, Hannah AL, Hudis CA (2007) Combination of trastuzumab and tanespimycin (17-AAG, KOS-593) is safe and active in trastuzumab-refractory HER-2-overexpressing breast cancer: a Phase I dose escalation study. J Clin Oncol 25:5410-5417 (Pubitemid 350232217)
93. Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K, Rice J, Barabasz A, Foley B, Ikeda H, Raje N, Kiziltepe T, Yasui H, Enatsu S, Anderson KC (2009) SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood 113:846-855
94. Okuzumi T, Fiedler D, Zhang C, Gray DC, Aizenstein B, Hoffman R, Shokat KM (2009) Inhibitor hijacking of Akt activation. Nat Chem Biol 5:484-493
95. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD, Silengo L, Altruda F, Wetzker R, Wymann MP, Lembo G, Hirsch E (2004) PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118:375-387 (Pubitemid 39061117)
96. Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C, Zalkow L, Matter WF, Dodge J, Grindey G (1994) Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54:2419-2423
97. Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang S-Y, Robell K et al (2008) Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 68:2366-2374 (Pubitemid 351521811)
98. Ruiter GA, Zerp SF, Bartelin H, Van Blitterswijk WJ, Verheij M (2003) Anti-cancer alkyllysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs 14:167-173 (Pubitemid 36269756)
99. Sadhu C, Dick K, Tino WT, Staunton DE (2003) Selective role of PI3Kd in neutrophil inflammatory responses. Biochem Biophys Res Commun 308:764-769 (Pubitemid 36976527)
100. Safa O, Parkin SM, Bibby MC (1998) Morphological cahnges and cytokine gene expression in tumor xenografts following treatment with alkylphosphocholines hexadecylphosphocholine and perifosine. Drugs Today 34:15-26 (Pubitemid 29046792)
101. Sarbassov D, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/ PKB by the rictor-mTOR complex. Science 307:1098-1101 (Pubitemid 40262113)
102. Sarker D, Kristeleit R, Mazina KE, Ware JA, Yan Y, Dresser M, Derynck MK, De-Bono J (2009) A phase I study evaluating the pharmacokinetics (PK) and pharmacodynamics (PD) of the oral pan-phosphoinositide-3 kinase (PI3K) inhibitor GDC-0941. J Clin Oncol (Meeting Abstracts) 27:3538
103. Seipelt I, Claus E, Schuster T, Polymeropoulos E, Teifel M, Guenther E (2007) New generation of anilino-substituted pyridopyrazine-urea derivatives show highly selective PI3K-inhibition. AACR Meeting Abstracts 2007:2379
104. Seipelt I, Baasner S, Gerlach M, Teifel M, Fensterle J, Blumenstein L, Mueller G, Guenther EG (2009) AEZS-126, a new orally bioavailable PI3K inhibitor in preclinical development (poster). Presented at 100th AACR annual meeting, Denver, USA, 18-22 April 2009
105. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di CS, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J (2008) NVPBEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022-8030
106. Shapiro G, Kwak E, Baselga J, Rodon J, Scheffold C, Laird AD, Bedell C, Edelman G (2009) Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors. J Clin Oncol (Meeting Abstracts) 27:3500
107. Shi Y, Liu X, Han E, Guan R, Shoemaker AR, Oleksijew A, Woods KW, Fisher JP, Klinghofer V, Lasko L, McGonigal T, Li Q, Rosenberger SH, Giranda VL, Luo Y (2005) Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Noeplasia 7:992-1000
108. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N (2003) Inhibition of Heat Shock Protein 90 Function Down-Regulates Akt Kinase and Sensitizes Tumors to Taxol. Cancer Res 63:2139-2144 (Pubitemid 36538618)
109. Stauffer F, Maira SM, Furet P, Garcia-Echeverria C (2008) Imidazo[4,5-c]quinolines as inhibitors of the PI3K/PKB-pathway. Bioorg Med Chem Lett 18:1027-1030 (Pubitemid 351187880)
110. Stümer T, Zöllinger A, Siegmund D, Chatterjee M, Grella E, Knop S, Kortüm M et al (2008) Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22:1604-1612
111. Sydor J, Normant E, Pien CS, Porter JR, Ge J, Grenier L, Park RH, Ali JA, Dembski MS et al (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA 103:17408-17413 (Pubitemid 44788982)
112. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, Reichling LJ, Sim T, Sabatini DM, Gray NS (2009) An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023-8032
113. Tian ZQ, Liu Y, Zhang D, Wang Z, Dong SD, Carreras CW, Zhou Y, Rastelli G, Santi DV, Myles DC (2004) Synthesis and biological activities of novel 17-aminogeldanamycin derivatives. Bioorg Med Chem 12:5317-5329 (Pubitemid 39243952)
114. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267-272 (Pubitemid 27310948)
115. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC (2005) Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci 30:194-204 (Pubitemid 40463309)
116. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241-5248
117. Wagner AJ, Von Hoff DH, LoRusso PM, Tibes R, Mazina KE, Ware JA, Yan Y, Derynck MK, Demetri GD (2009) A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 27:3501
118. Walker EH, Perisic O, Ried C, Stephens L, Williams RL (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402:313-320 (Pubitemid 129516270)
119. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6:909-919
120. Ward SG, Finan P (2003) Isoform-specific phosphoinositide 3-kinase
121. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, Stegmeier F, Yao YM, Lengauer C (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105:13057-13062
122. Whitesell L, Lindquist SL (2005) Hsp90 and the chaperoning of cancer. Nat Rev 5:761-772 (Pubitemid 41400776)
123. Williams R, Baker AF, Ihle NT, Winkler AR, Kirkpatrick L, Powis G (2006) The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother Pharmacol 58:444-450 (Pubitemid 43999792)
124. Williams R, Berndt A, Miller S, Hon WC, Zhang X (2009) Form and flexibility in phosphoinositide 3-kinases. Biochem Soc Trans 37:615-626
125. Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T (2006) Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst 98:545-556 (Pubitemid 43898818)
126. Yao E, Zhou W, Lee-Hoeflich ST, Truong T, Haverty PM, Eastham-Anderson J, Lewin-Koh N, Gunter B, Belvin M, Murray LJ, Friedman LS, Sliwkowski MX, Hoeflich KP (2009) Suppression of HER2/HER3-mediated growth of breast cancer cells with combinations of GDC-0941 PI3K inhibitor, trastuzumab, and pertuzumab. Clin Cancer Res 15:4147-4156
127. Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B, Kim J, Verheijen J, Curran K, Malwitz DJ, Cole DC, Ellingboe J, Ayral-Kaloustian S, Mansour TS, Gibbons JJ, Abraham RT, Nowak P, Zask A (2009) Biochemical, cellular, and in vivo activity of novel ATPcompetitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69:6232-6240
128. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497-5510
129. Zask A, Verheijen JC, Curran K, Kaplan J, Richard DJ, Nowak P, Malwitz DJ, Brooijmans N, Bard J, Svenson K, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham RT, Ayral-Kaloustian S, Mansour TS, Yu K (2009a) ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines. J Med Chem 52:5013-5016
130. Zask A, Verheijen J, Kaplan J, Curran K, Richard DJ, Brooijmans N, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham R (2009b) ATP competitive inhibitors of the mammalian target of rapamycin (mTOR): design and synthesis of novel, highly selective pyrazolopyrimidines with potent in vivo antitumor activity. Presented at 100th AACR annual meeting, Denver, USA, 18-22 April 2009
131. Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, Vanhaesebroeck B, Marshall AJ (2008) Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol 122:811-819
132. Zhao L, Vogt PK (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486-5496
133. Zhao Z, Leister WH, Robinson RG, Stanley FB, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME, Lindsley CW (2005) Discovery of 2,3,5-trisubstitued pyridine derivatives as potent Akt and Akt2 dual inhibitors. Bioorg Med Chem Lett 15: 905-909 (Pubitemid 40458621)
134. Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A, Roberts TM (2006) The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci USA 103:16296-16300 (Pubitemid 44715190)
135. Zhao Z, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huber HE, Duggan ME, Lindsley CW (2008) Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity. Bioorg Med Chem Lett 18:49-53
136. Zhu GD, Gandhi VB, Gong J, Thomas S, Woods KW, Song X, Li T, Diebold RB et al (2007) Synthesis of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J Med Chem 50:2990-3003 (Pubitemid 47001242)