Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)

International Journal of Oncology

Volumn 48, Issue 3, 2016, Pages 869-885

  Nitulescu, George Mihai ^a   Margina, Denisa ^a   Juzenas, Petras ^b   Peng, Qian ^b   Olaru, Octavian Tudorel ^a   Saloustros, Emmanouil ^c   Fenga, Concettina ^d   Spandidos, Demetrios A ^e   Libra, Massimo ^f   Tsatsakis, Aristidis M ^e  

^a CAROL DAVILA UNIVERSITY OF MEDICINE AND PHARMACY   (Romania)

^b OSLO UNIVERSITY HOSPITAL   (Norway)

^c Venizelio General Hospital of Heraklion   (Greece)

^d UNIVERSITY OF MESSINA   (Italy)

^e UNIVERSITY OF CRETE   (Greece)

^f UNIVERSITY OF CATANIA   (Italy)

Author keywords

Afuresertib; ATPcompetitive inhibitors; AZD5363; Ipatasertib; MK 2206; Perifosine; PH domain; Phosphatase and tensin homolog; Triciribine; Uprosertib

Indexed keywords

2,3 DIPHENYLQUINOXALINE DERIVATIVE; 3 INDOLEMETHANOL; 4 AMINO N [1 (4 CHLOROPHENYL) 3 HYDROXYPROPYL] 1 (7H PYRROLO[2,3 D]PYRIMIDIN 4 YL) 4 PIPERIDINECARBOXAMIDE; 4 [2 (4 AMINO 1,2,5 OXADIAZOL 3 YL) 1 ETHYL 7 (3 PIPERIDINYLMETHOXY) 1H IMIDAZO[4,5 C]PYRIDIN 4 YL] 2 METHYL 3 BUTYN 2 OL; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AFURESERTIB; ALKYLPHOSPHOLIPID DERIVATIVE; AMIDE; ANTINEOPLASTIC AGENT; AZEPANE DERIVATIVE; EDELFOSINE; ERUCYLPHOSPHOCHOLINE; HETEROCYCLIC COMPOUND; IPATASERTIB; ISOQUINOLINE 5 SULFONAMIDE DERIVATIVE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; PURINE DERIVATIVE; PYRAZOLE DERIVATIVE; SULFONAMIDE; THIOPHENECARBOXAMIDE DERIVATIVE; THIOUREA DERIVATIVE; UNCLASSIFIED DRUG; UPROSERTIB; ADENOSINE TRIPHOSPHATE; AKT1 PROTEIN, HUMAN; ENZYME INHIBITOR; ISOPROTEIN;

ALLOSTERISM; CANCER GROWTH; CELL CYCLE PROGRESSION; CELL DIFFERENTIATION; CELL GROWTH; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; HIGH THROUGHPUT SCREENING; HUMAN; METASTASIS; MOLECULARLY TARGETED THERAPY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN STRUCTURE; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; X RAY CRYSTALLOGRAPHY; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; BINDING SITE; CATALYSIS; CHEMISTRY; CLINICAL TRIAL (TOPIC); DRUG DESIGN; ENZYME ACTIVE SITE; ENZYMOLOGY; GENE EXPRESSION REGULATION; METABOLISM; NEOPLASMS;

ADENOSINE TRIPHOSPHATE; ALLOSTERIC SITE; ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CATALYSIS; CATALYTIC DOMAIN; CELL PROLIFERATION; CLINICAL TRIALS AS TOPIC; DRUG DESIGN; ENZYME INHIBITORS; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NEOPLASMS; PROTEIN ISOFORMS; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION;

EID: 84959017186     PISSN: 10196439     EISSN: 17912423     Source Type: Journal    
DOI: 10.3892/ijo.2015.3306     Document Type: Review

References (147)

1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136: E359-E386, 2015
2. Siegel R, Ma J, Zou Z and Jemal A. Cancer statistics, 2014. CA Cancer J Clin 64: 9-29, 2014
3. Steelman LS, Stadelman KM, Chappell WH, Horn S, Bäsecke J, Cervello M, Nicoletti F, Libra M, Stivala F, Martelli AM, et al. Akt as a therapeutic target in cancer. Expert Opin Ther Targets 12: 1139-1165, 2008
4. Bellacosa A, Kumar CC, Di Cristofano A and Testa JR. Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv Cancer Res 94: 29-86, 2005
5. Arcaro A and Guerreiro AS. The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr Genomics 8: 271-306, 2007
6. Mitsiades CS, Mitsiades N and Koutsilieris M. The Akt pathway: Molecular targets for anti-cancer drug development. Curr Cancer Drug Targets 4: 235-256, 2004
7. Altomare DA and Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 24: 7455-7464, 2005
8. Song G, Ouyang G and Bao S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9: 59-71, 2005
9. Martelli AM, Tabellini G, Bressanin D, Ognibene A, Goto K, Cocco L and Evangelisti C. The emerging multiple roles of nuclear Akt. Biochim Biophys Acta-Mol. Cell Res 1823: 2168-2178, 2012
10. Arencibia JM, Pastor-Flores D, Bauer AF, Schulze JO and Biondi RM. AGC protein kinases: From structural mechanism of regulation to allosteric drug development for the treatment of human diseases. Biochim Biophys Acta 1834: 1302-1321, 2013
11. Davis WJ, Lehmann PZ and Li W. Nuclear PI3K signaling in cell growth and tumorigenesis. Front Cell Dev Biol 3: 24, 2015
12. Sasaki T, Yamashita Y and Kuniyasu H. AKT plays a crucial role in gastric cancer (Review). Oncol Lett 10: 607-611, 2015
13. Shayesteh L, Lu Y, Kuo W-L, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21: 99-102, 1999
14. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI and Boyd J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11: 2875-2878, 2005
15. Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM and Hemmings BA. Role of translocation in the activation and function of protein kinase B. J Biol Chem 272: 31515-31524, 1997
16. Carnero A and Paramio JM. The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. Front Oncol 4: 252, 2014
17. Conus NM, Hannan KM, Cristiano BE, Hemmings BA and Pearson RB. Direct identification of tyrosine 474 as a regulatory phosphorylation site for the Akt protein kinase. J Biol Chem 277: 38021-38028, 2002
18. Legate KR, Montañez E, Kudlacek O and Fässler R. ILK, PINCH and parvin: The tIPP of integrin signalling. Nat Rev Mol Cell Biol 7: 20-31, 2006
19. Jhaveri K and Modi S. Ganetespib: Research and clinical development. Onco Targets Ther 8: 1849-1858, 2015
20. O'Neill AK, Niederst MJ and Newton AC. Suppression of survival signalling pathways by the phosphatase PHLPP. FEBS J 280: 572-583, 2013
21. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C and González-Barón M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30: 193-204, 2004
22. Altomare DA and Khaled AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem 19: 3748-3762, 2012
23. Cohen MM Jr. The AKT genes and their roles in various disorders. Am J Med Genet A 161A: 2931-2937, 2013
24. Emamian ES. AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci 5: 33, 2012
25. Mackenzie RWA and Elliott BT. Akt/PKB activation and insulin signaling: A novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes 7: 55-64, 2014
26. Osorio-Fuentealba C and Klip A. Dissecting signalling by individual Akt/PKB isoforms, three steps at once. Biochem J 470: e13-e16, 2015
27. Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, Lee VM, Szabolcs M, de Jong R, Oltersdorf T, et al. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol 25: 1869-1878, 2005
28. West KA, Castillo SS and Dennis PA. Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat 5: 234-248, 2002
29. Candido S, Rapisarda V, Marconi A, Malaponte G, Bevelacqua V, Gangemi P, Scalisi A, McCubrey JA, Maestro R, Spandidos DA, et al. Analysis of the B-RafV600E mutation in cutaneous melanoma patients with occupational sun exposure. Oncol Rep 31: 1079-1082, 2014
30. Shi Y, Liu X, Han EK, Guan R, Shoemaker AR, Oleksijew A, Woods KW, Fisher JP, Klinghofer V, Lasko L, et al. Optimal classes of chemotherapeutic agents sensitized by specific small-molecule inhibitors of akt in vitro and in vivo. Neoplasia 7: 992-1000, 2005
31. Hafsi S, Pezzino FM, Candido S, Ligresti G, Spandidos DA, Soua Z, McCubrey JA, Travali S and Libra M. Gene alterations in the PI3K/PTEN/AKT pathway as a mechanism of drug-resistance (Review). Int J Oncol 40: 639-644, 2012
32. Carnero A. The PKB/AKT pathway in cancer. Curr Pharm Des 16: 34-44, 2010
33. Nagata Y, Lan K-H, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al. PTEN activation contributes to tumor inhibition by trastuzumab and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6: 117-127, 2004
34. Fujita T, Doihara H, Washio K, Kawasaki K, Takabatake D, Takahashi H, Tsukuda K, Ogasawara Y and Shimizu N. Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells. Anticancer Drugs 17: 455-462, 2006
35. Olaru OT, Ni?ulescu GM, Or?an A and Dinu-Pîrvu CE. Ethnomedicinal, Phytochemical and Pharmacological Profile of Anthriscus sylvestris as an Alternative Source for Anticancer Lignans. Molecules 20: 15003-15022, 2015
36. Peuhu E, Rivero-Müller A, Stykki H, Torvaldson E, Holmbom T, Eklund P, Unkila M, Sjöholm R and Eriksson JE. Inhibition of Akt signaling by the lignan matairesinol sensitizes prostate cancer cells to TRAIL-induced apoptosis. Oncogene 29: 898-908, 2010
37. Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike-Wada O, et al. The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer 101: 145-148, 2009
38. Rychahou PG, Kang J, Gulhati P, Doan HQ, Chen LA, Xiao SY, Chung DH and Evers BM. Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. Proc Natl Acad Sci USA 105: 20315-20320, 2008
39. Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, Paul JD, Hbaiu A, Goode RG, Sandusky GE, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J Biol Chem 275: 24500-24505, 2000
40. Altomare DA, Tanno S, De Rienzo A, Klein-Szanto AJ, Tanno S, Skele KL, Hoffman JP and Testa JR. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J Cell Biochem 87: 470-476, 2002
41. Lin HP, Lin CY, Huo C, Jan YJ, Tseng JC, Jiang SS, Kuo YY, Chen SC, Wang CT, Chan TM, et al. AKT3 promotes prostate cancer proliferation cells through regulation of Akt, B-Raf and TSC1/TSC2. Oncotarget 6: 27097-27112, 2015
42. Cristiano BE, Chan JC, Hannan KM, Lundie NA, Marmy-Conus NJ, Campbell IG, Phillips WA, Robbie M, Hannan RD and Pearson RB A specific role for AKT3 in the genesis of ovarian cancer through modulation of G(2)-M phase transition. Cancer Res 66: 11718-11725, 2006
43. Mattmann ME, Stoops SL and Lindsley CW. Inhibition of Akt with small molecules and biologics: Historical perspective and current status of the patent landscape. Expert Opin Ther Pat 21: 1309-1338, 2011
44. Kumar CC and Madison V. AKT crystal structure and AKT-specific inhibitors. Oncogene 24: 7493-7501, 2005
45. Böckmann S and Nebe B. The in vitro effects of H-89, aspecific inhibitor of protein kinase A, in the human colonic carcinoma cell line Caco-2. Eur J Cancer Prev 12: 469-478, 2003
46. Reuveni H, Livnah N, Geiger T, Klein S, Ohne O, Cohen I, Benhar M, Gellerman G and Levitzki A. Toward a PKB inhibitor: Modification of a selective PKA inhibitor by rational design. Biochemistry 41: 10304-10314, 2002
47. Breitenlechner CB, Wegge T, Berillon L, Graul K, Marzenell K, Friebe WG, Thomas U, Schumacher R, Huber R, Engh RA, et al. Structure-based optimization of novel azepane derivatives as PKB inhibitors. J Med Chem 47: 1375-1390, 2004
48. Murray AJ. Pharmacological PKA inhibition: All may not be what it seems. Sci Signal 1: re4-re4, 2008
49. Heerding DA, Rhodes N, Leber JD, Clark TJ, Keenan RM, Lafrance LV, Li M, Safonov IG, Takata DT, Venslavsky JW, et al. Identification of 4-(2-(4-Amino-1, 2, 5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4, 5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), anovel inhibitor of AKT kinase. J Med Chem 51: 5663-5679, 2008
50. Levy DS, Kahana JA and Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 113: 1723-1729, 2009
51. Carol H, Morton CL, Gorlick R, Kolb EA, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA, et al. Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program. Pediatr Blood Cancer 55: 1329-1337, 2010
52. Crouthamel MC, Kahana JA, Korenchuk S, Zhang SY, Sundaresan G, Eberwein DJ, Brown KK and Kumar R. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res 15: 217-225, 2009
53. Donald A, McHardy T, Rowlands MG, Hunter LJ, Davies TG, Berdini V, Boyle RG, Aherne GW, Garrett MD and Collins I. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. J Med Chem 50: 2289-2292, 2007
54. Caldwell JJ, Davies TG, Donald A, McHardy T, Rowlands MG, Aherne GW, Hunter LK, Taylor K, Ruddle R, Raynaud FI, et al. Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2, 3-d] pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J Med Chem 51: 2147-2157, 2008
55. Yap TA, Walton MI, Hunter L.-J.K, Valenti M, de Haven Brandon A, Eve PD, Ruddle R, Heaton SP, Henley A, Pickard L, et al. Preclinical pharmacology, antitumor activity and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol Cancer Ther 10: 360-371, 2011
56. Freeman-Cook KD, Autry C, Borzillo G, Gordon D, Barbacci-Tobin E, Bernardo V, Briere D, Clark T, Corbett M, Jakubczak J, et al. Design of selective, ATP-competitive inhibitors of Akt. J Med Chem 53: 4615-4622, 2010
57. Lippa B, Pan G, Corbett M, Li C, Kauffman GS, Pandit J, Robinson S, Wei L, Kozina E, Marr ES, et al. Synthesis and structure based optimization of novel Akt inhibitors. Bioorg Med Chem Lett 18: 3359-3363, 2008
58. McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, Ruddle R, Henley A, de Haven Brandon A, Valenti M, et al. Discovery of 4-Amino-1-(7H-pyrrolo[2, 3-d] pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J Med Chem 53: 2239-2249, 2010
59. Addie M, Ballard P, Buttar D, et al. Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2, 3-d] pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem 56: 2059-2073, 2013
60. Crafter C, Vincent JP, Tang E, Dudley P, James NH, Klinowska T and Davies BR. Combining AZD8931, anovel EGFR/HER2/HER3 signalling inhibitor, with AZD5363 limits AKT inhibitor induced feedback and enhances antitumour efficacy in HER2-Amplified breast cancer models. Int J Oncol 47: 446-454, 2015
61. Lamoureux F and Zoubeidi A. Dual inhibition of autophagy and the AKT pathway in prostate cancer. Autophagy 9: 1119-1120, 2013
62. Blake JF, Xu R, Bencsik JR, Xiao D, Kallan NC, Schlachter S, Mitchell IS, Spencer KL, Banka AL, Wallace EM, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem 55: 8110-8127, 2012
63. Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, et al. Targeting activated Akt with GDC-0068, anovel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res 19: 1760-1772, 2013
64. Kim S, Tan AR, Im S, Villanueva R, Valero V, Saura C, Oliveira M, Isakoff SJ, Singel SM and Dent RA. LOTUS: A randomized, phase II, multicenter, placebo-controlled study of ipatasertib (Ipat, GDC-0068), an inhibitor of Akt, in combination with paclitaxel (Pac) as front-line treatment for patients (pts) with metastatic triple-negative breast cancer (TNBC). ASCO Meet Abstr 33: TPS1111, 2015
65. Luo Y, Shoemaker AR, Liu X, Woods KW, Thomas SA, de Jong R, Han EK, Li T, Stoll VS, Powlas JA, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther 4: 977-986, 2005
66. Woods KW, Fischer JP, Claiborne A, Li T, Thomas SA, Zhu GD, Diebold RB, Liu X, Shi Y, Klinghofer V, et al. Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors. Bioorg Med Chem 14: 6832-6846, 2006
67. Lin H, Yamashita DS, Xie R, Zeng J, Wang W, Leber J, Safonov IG, Verma S, Li M, Lafrance L, et al. Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines. Bioorg Med Chem Lett 20: 684-688, 2010
68. Ko JH, Yeon SW, Ryu JS, Kim TY, Song EH, You HJ, Park RE and Ryu CK. Synthesis and biological evaluation of 5-Arylamino-6-chloro-1H-indazole-4, 7-diones as inhibitors of protein kinase B/Akt. Bioorg Med Chem Lett 16: 6001-6005, 2006
69. Bencsik JR, Xiao D, Blake JF, Kallan NC, Mitchell IS, Spencer KL, Xu R, Gloor SL, Martinson M, Risom T, et al. Discovery of dihydrothieno-And dihydrofuropyrimidines as potent pan Akt inhibitors. Bioorg Med Chem Lett 20: 7037-7041, 2010
70. Saxty G, Woodhead SJ, Berdini V, Davies TG, Verdonk ML, Wyatt PG, Boyle RG, Barford D, Downham R, Garrett MD, et al. Identification of inhibitors of protein kinase B using fragment-based lead discovery. J Med Chem 50: 2293-2296, 2007
71. Grimshaw KM, Hunter L-JK, Yap TA, Heaton SP, Walton MI, Woodhead SJ, Fazal L, Reule M, Davies TG, Seavers LC, et al. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol Cancer Ther 9: 1100-1110, 2010
72. Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, et al. AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity. Clin Cancer Res 18: 3912-3923, 2012
73. Lin X, Murray JM, Rico AC, Wang MX, Chu DT, Zhou Y, Del Rosario M, Kaufman S, Ma S, Fang E, et al. Discovery of 2-pyrimidyl-5-Amidothiophenes as potent inhibitors for AKT: Synthesis and SAR studies. Bioorg Med Chem Lett 16: 4163-4168, 2006
74. Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, Liu Q, Figueroa DJ, Minthorn EA, Seefeld MA, et al. Discovery of novel AKT inhibitors with enhanced anti-Tumor effects in combination with the MEK inhibitor. PLoS One 9: e100880, 2014
75. Chang S, Zhang Z, Zhuang X, Luo J, Cao X, Li H, Tu Z, Lu X, Ren X and Ding K. New thiazole carboxamides as potent inhibitors of Akt kinases. Bioorg Med Chem Lett 22: 1208-1212, 2012
76. Deng R, Yang F, Chang SH, Tang J, Qin J, Feng GK, Ding K and Zhu XF. DC120, anovel and potent inhibitor of AKT kinase, induces tumor cell apoptosis and suppresses tumor growth. Mol Pharmacol 82: 189-198, 2012
77. Spencer A, Yoon SS, Harrison SJ, Morris SR, Smith DA, Brigandi RA, Gauvin J, Kumar R, Opalinska JB and Chen C. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics and clinical activity in multiple myeloma. Blood 124: 2190-2195, 2014
78. Faiman B and Richards T. Innovative agents in multiple myeloma. J Adv Pract Oncol 5: 193-202, 2014
79. Wu WI, Voegtli WC, Sturgis HL, Dizon FP, Vigers GPA and Brandhuber BJ. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLoS One 5: e12913, 2010
80. Lu S, Li S and Zhang J. Harnessing allostery: A novel approach to drug discovery. Med Res Rev 34: 1242-1285, 2014
81. Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huff JR, Huber HE, et al. Allosteric Akt (PKB) inhibitors: Discovery and SAR of isozyme selective inhibitors. Bioorg Med Chem Lett 15: 761-764, 2005
82. Bilodeau MT, Balitza AE, Hoffman JM, Manley PJ, Barnett SF, Defeo-Jones D, Haskell K, Jones RE, Leander K, Robinson RG, et al. Allosteric inhibitors of Akt1 and Akt2: A naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg Med Chem Lett 18: 3178-3182, 2008
83. Li Y, Liang J, Siu T, Hu E, Rossi MA, Barnett SF, Defeo-Jones D, Jones RE, Robinson RG, Leander K, et al. Allosteric inhibitors of Akt1 and Akt2: Discovery of [1, 2, 4]triazolo[3, 4-f][1, 6]naphthyridines with potent and balanced activity. Bioorg Med Chem Lett 19: 834-836, 2009
84. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder PK, Pan BS, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9: 1956-1967, 2010
85. Fang Z, Simard JR, Plenker D, Nguyen HD, Phan T, Wolle P, Baumeister S and Rauh D. Discovery of inter-domain stabilizers-A novel assay system for allosteric akt inhibitors. ACS Chem Biol 10: 279-288, 2015
86. Jiao P, Zhou YS, Yang JX, Zhao YL, Liu QQ, Yuan C and Wang FZ. MK-2206 induces cell cycle arrest and apoptosis in HepG2 cells and sensitizes TRAIL-mediated cell death. Mol Cell Biochem 382: 217-224, 2013
87. Molife LR, Yan L, Vitfell-Rasmussen J, Zernhelt AM, Sullivan DM, Cassier PA, Chen E, Biondo A, Tetteh E, Siu LL, et al. Phase 1 trial of the oral AKT inhibitor MK-2206 plus carboplatin/paclitaxel, docetaxel, or erlotinib in patients with advanced solid tumors. J Hematol Oncol 7: 1, 2014
88. Kümler I, Tuxen MK and Nielsen DL A systematic review of dual targeting in HER2-positive breast cancer. Cancer Treat Rev 40: 259-270, 2014
89. Konopleva MY, Walter RB, Faderl SH, Jabbour EJ, Zeng Z, Borthakur G, Huang X, Kadia TM, Ruvolo PP, Feliu JB, et al. Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin Cancer Res 20: 2226-2235, 2014
90. Do K, Speranza G, Bishop R, Khin S, Rubinstein L, Kinders RJ, Datiles M, Eugeni M, Lam MH, Doyle LA, et al. Biomarker-driven phase 2 study of MK-2206 and selumetinib (AZD6244, ARRY-142886) in patients with colorectal cancer. Invest New Drugs 33: 720-728, 2015
91. Meuillet EJ. Novel inhibitors of AKT: Assessment of a different approach targeting the pleckstrin homology domain. Curr Med Chem 18: 2727-2742, 2011
92. Gills JJ a nd D ennis PA. Perifosine: Update on a novel A kt inhibitor. Curr Oncol Rep 11: 102-110, 2009
93. van Blitterswijk WJ and Verheij M. Anticancer mechanisms and clinical application of alkylphospholipids. Biochim Biophys Acta 1831: 663-674, 2013
94. van der Luit AH, Vink SR, Klarenbeek JB, Perrissoud D, Solary E, Verheij M and van Blitterswijk WJ A new class of anticancer alkylphospholipids uses lipid rafts as membrane gateways to induce apoptosis in lymphoma cells. Mol Cancer Ther 6: 2337-2345, 2007
95. Reis-Sobreiro M, Roué G, Moros A, Gajate C, de la Iglesia-Vicente J, Colomer D and Mollinedo F. Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma. Blood Cancer J 3: e118, 2013
96. Pachioni J, de A, Magalhães JG, Lima EJC, Bueno L, de M, Barbosa JF, de Sá MM and Rangel-Yagui CO. Alkylphospholipids-A promising class of chemotherapeutic agents with a broad pharmacological spectrum. J Pharm Pharm Sci 16: 742-759, 2013
97. Giantonio BJ, Derry C, McAleer C, McPhillips JJ and O'Dwyer PJ. Phase I and pharmacokinetic study of the cytotoxic ether lipid ilmofosine administered by weekly two-hour infusion in patients with advanced solid tumors. Clin Cancer Res 10: 1282-1288, 2004
98. Verweij J, Krzemieniecki K, Kok T, Poveda A, van Pottelsberghe C, van Glabbeke M and Mouridsen H. Phase II study of miltefosine (hexadecylphosphocholine) in advanced soft tissue sarcomas of the adult-An EORTC Soft Tissue and Bone Sarcoma Group Study. Eur J Cancer 29A: 208-209, 1993
99. Becher R, Kloke K, Füger A, Bremer K, Drozd A, Kleeberg UR, Fritze D, Rieche K and Sindermann H. Phase II Trial of Orally Administered Miltefosine in Advanced Colorectal Cancer. Onkologie 16: 11-15, 1993
100. Clive S, Gardiner J and Leonard RCF. Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother Pharmacol Suppl 44, 2000
101. Dorlo TPC, Balasegaram M, Beijnen JH and de Vries PJ. Miltefosine: A review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother 67: 2576-2597, 2012
102. Orlowski RZ. Novel agents for multiple myeloma to overcome resistance in phase III clinical trials. Semin Oncol 40: 634-651, 2013
103. Henke G, Lindner LH, Vogeser M, Eibl HJ, Wörner J, Müller AC, Bamberg M, Wachholz K, Belka C and Jendrossek V : Pharmacokinetics and biodistribution of Erufosine in nude mice-implications for combination with radiotherapy Radiat Oncol 4 46 2009
104. Rübel A, Handrick R, Lindner LH, Steiger M, Eibl H, Budach W, Belka C and Jendrossek V. The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro. Radiat Oncol 1: 6, 2006
105. Kaleaʇas?oʇlu F and Berger MR. Differential effects of erufosine on proliferation, wound healing and apoptosis in colorectal cancer cell lines. Oncol Rep 31: 1407-1416, 2014
106. Rudner J, Ruiner CE, Handrick R, Eibl HJ, Belka C and Jendrossek V. The Akt-inhibitor Erufosine induces apoptotic cell death in prostate cancer cells and increases the short term effects of ionizing radiation. Radiat Oncol 5: 108, 2010
107. Chinni SR and Sarkar FH. Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 8: 1228-1236, 2002
108. Aggarwal BB and Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 4: 1201-1215, 2005
109. Kim DJ, Reddy K, Kim MO, Li Y, Nadas J, Cho YY, Kim JE, Shim JH, Song NR, Carper A, et al. (3-Chloroacetyl)-indole, anovel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo. Cancer Prev Res (Phila) 4: 1842-1851, 2011
110. Chao WR, Yean D, Amin K, Green C and Jong L. Computer-Aided rational drug design: A novel agent (SR13668) designed to mimic the unique anticancer mechanisms of dietary indole-3-carbinol to block Akt signaling. J Med Chem 50: 3412-3415, 2007
111. Kapetanovic IM, Muzzio M, Hu S-C, Crowell JA, Rajewski RA, Haslam JL, Jong L and McCormick DL. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys. Cancer Chemother Pharmacol 65: 1109-1116, 2010
112. Reid JM, Walden CA, Qin R, Ziegler KL, Haslam JL, Rajewski RA, Warndahl R, Fitting CL, Boring D, Szabo E, et al; Cancer Prevention Network: Phase 0 clinical chemoprevention trial of the Akt inhibitor SR13668 Cancer Prev Res (Phila) 4 347-353 2011
113. Weng JR, Tsai CH, Omar HA, Sargeant AM, Wang D, Kulp SK, Shapiro CL and Chen CS. OSU-A9, apotent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling. Carcinogenesis 30: 1702-1709, 2009
114. Mahadevan D, Powis G, Mash EA, George B, Gokhale VM, Zhang S, Shakalya K, Du-Cuny L, Berggren M, Ali MA, et al. Discovery of a novel class of AKT pleckstrin homology domain inhibitors. Mol Cancer Ther 7: 2621-2632, 2008
115. Moses SA, Ali MA, Zuohe S, Du-Cuny L, Zhou LL, Lemos R, Ihle N, Skillman AG, Zhang S, Mash EA, et al. In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT. Cancer Res 69: 5073-5081, 2009
116. Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L, Herbst R. Molecular pharmacology and antitumor activity of PHT-427, anovel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther 9: 706-717, 2010
117. Miao B, Skidan I, Yang J, Lugovskoy A, Reibarkh M, Long K, Brazell T, Durugkar KA, Maki J, Ramana CV, et al. Small molecule inhibition of phosphatidylinositol-3, 4, 5-Triphosphate (PIP3) binding to pleckstrin homology domains. Proc Natl Acad Sci USA 107: 20126-20131, 2010
118. Kommagalla Y, Cornea S, Riehle R, Torchilin V, Degterev A and Ramana CV. Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: Switching a thiourea with 1, 2, 3-Triazole. MedChemComm 5: 1359-1363, 2014
119. Nitulescu GM, Draghici C, Olaru OT, Matei L, Ioana A, Dragu L D and Bleotu C. Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines. Bioorg Med Chem 23: 5799-5808, 2015
120. Yang L, Dan HC, Sun M, Liu Q, Sun XM, Feldman RI, Hamilton AD, Polokoff M, Nicosia SV, Herlyn M, et al. Akt/protein kinase B signaling inhibitor-2, aselective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res 64: 4394-4399, 2004
121. Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, Verstovsek S, Faderl S, Garcia-Manero G, List AF, et al. Phase I clinical, pharmacokinetic and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies. Leuk Res 37: 1461-1467, 2013
122. Berndt N, Yang H, Trinczek B, Betzi S, Zhang Z, Wu B, Lawrence NJ, Pellecchia M, Schönbrunn E, Cheng JQ, et al. The Akt activation inhibitor TCN-P inhibits Akt phosphorylation by binding to the PH domain of Akt and blocking its recruitment to the plasma membrane. Cell Death Differ 17: 1795-1804, 2010
123. Evangelisti C, Ricci F, Tazzari P, Chiarini F, Battistelli M, Falcieri E, Ognibene A, Pagliaro P, Cocco L, McCubrey JA, et al. Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia. J Cell Physiol 226: 822-831, 2011
124. Dieterle A, Orth R, Daubrawa M, Grotemeier A, Alers S, Ullrich S, Lammers R, Wesselborg S and Stork B. The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL-induced apoptosis. Int J Cancer 125: 932-941, 2009
125. Kim R, Yamauchi T, Husain K, Sebti S and Malafa M. Triciribine Phosphate Monohydrate, an AKT Inhibitor, Enhances Gemcitabine Activity in Pancreatic Cancer Cells. Anticancer Res 35: 4599-4604, 2015
126. Kim D, Sun M, He L, Zhou QH, Chen J, Sun XM, Bepler G, Sebti SM and Cheng JQ A small molecule inhibits Akt through direct binding to Akt and preventing Akt membrane translocation. J Biol Chem 285: 8383-8394, 2010
127. Li B, Ren H, Yue P, Chen M, Khuri FR and Sun SY. The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition. Cancer Prev Res (Phila) 5: 612-620, 2012
128. Ashwell MA, Lapierre J-M, Brassard C, Bresciano K, Bull C, Cornell-Kennon S, Eathiraj S, France DS, Hall T, Hill J, et al. Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4, 5-b]pyridin-2-yl)pyridin-2-Amines: Orally bioavailable, selective and potent ATP-independent Akt inhibitors. J Med Chem 55: 5291-5310, 2012
129. Chan TCK, Lapierre JM, Ashwell MA, France DS, Chen CR, Cornell-Kennon S, Bull C, Eathiraj S, Palma R, Liu Y, et al. Abstract A230: Discovery and characterization of ARQ 092, an ATP-independent, potent and selective inhibitor of AKT kinases. Mol Cancer Ther 10 (Suppl 1): A230-A230, 2011
130. Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, Hall T, Abbadessa G and Schwartz B. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. PLoS One 10: e0140479, 2015
131. Politz O, Scholz A, Haegebarth A, Liu N, Baerfacker L, Ince S, Neuhaus R, Boemer U, Michels M and Mumberg D. Abstract 3685: BAY 1125976, is a selective allosteric AKT1/2 inhibitor with high efficacy in AKT1-mutated cancers. Cancer Res 74 (Suppl 19): 3685, 2014
132. Yilmaz OG, Olmez EO and Ulgen KO. Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening. Comput Biol Chem 48: 1-13, 2014
133. Estrada AC, Syrovets T, Pitterle K, Lunov O, Büchele B, Schimana-Pfeifer J, Schmidt T, Morad SA and Simmet T. Tirucallic acids are novel pleckstrin homology domain-dependent Akt inhibitors inducing apoptosis in prostate cancer cells. Mol Pharmacol 77: 378-387, 2010
134. Morrow JK, Du-Cuny L, Chen L, Meuillet EJ, Mash EA, Powis G and Zhang S. Recent development of anticancer therapeutics targeting Akt. Recent Patents Anticancer Drug Discov 6: 146-159, 2011
135. Toral-Barza L, Zhang WG, Huang X, McDonald LA, Salaski E J, Barbieri LR, Ding WD, Krishnamurthy G, Hu YB, Lucas J, et al. Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: Mechanistic involvement of AKT catalytic activation loop cysteines. Mol Cancer Ther 6: 3028-3038, 2007
136. Salaski EJ, Krishnamurthy G, Ding WD, Yu K, Insaf SS, Eid C, Shim J, Levin JI, Tabei K, Toral-Barza L, et al. Pyranonaphthoquinone lactones: A new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine. J Med Chem 52: 2181-2184, 2009
137. Nguyen T, Coover RA, Verghese J, Moran RG and Ellis KC. Phenylalanine-Based Inactivator of AKT Kinase: Design, synthesis and biological evaluation. ACS Med Chem Lett 5: 462-467, 2014
138. Shearn CT, Reigan P and Petersen DR. Inhibition of hydrogen peroxide signaling by 4-hydroxynonenal due to differential regulation of Akt1 and Akt2 contributes to decreases in cell survival and proliferation in hepatocellular carcinoma cells. Free Radic Biol Med 53: 1-11, 2012
139. Weisner J, Gontla R, van der Westhuizen L, Oeck S, Ketzer J, Janning P, Richters A, Mühlenberg T, Fang Z, Taher A, et al. Covalent-Allosteric kinase inhibitors. Angew Chem Int Ed Engl 54: 10313-10316, 2015
140. She QB, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, Leander KR, DeFeo-Jones D, Huber HE and Rosen N. Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One 3: e3065, 2008
141. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, Miller TW, Arteaga CL, Mills GB, Gonzalez-Angulo AM and Meric-Bernstam F. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 18: 5816-5828, 2012
142. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity and correlation of monotherapy activity with genetic background. Mol Cancer Ther 11: 873-887, 2012
143. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, Baird RD, Delgado L, Taylor A, Lupinacci L, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 29: 4688-4695, 2011
144. Saura C, Jones S, Mateo J, Hollebecque A, Cleary JM, Perez DR, Zhu J, Musib LC, Patel PH, Cervantes-Ruiperez A, et al A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or mFOLFOX-6 (F) in patients (pts) with advanced solid tumors. J Clin Oncol 30 (Suppl; abstr 3021), 2012
145. Yan Y, Wagle M, Punnoose E, Musib L, Budha N, Nannini M, Lin K, Liederer BM, Murli S, Ramakrishnan V, et al A first-inhuman trial of GDC-0068: A novel, oral, ATP-competitive Akt inhibitor, demonstrates robust suppression of the Akt pathway in surrogate and tumor tissues. Mol Cancer Ther 10: abstr B154, 2011
146. Banerji U, Ranson M, Schellens J, Schellens JH, Esaki T, Dean E J and Zivi A. Results of two phase I multicenter trials of AZD5363, an inhibitor of AKT1, 2 and 3: Biomarker and early clinical evaluation in Western and Japanese patients with advanced solid tumors. Cancer Res 73: abstr LB-66, 2013
147. Dienstmann R, Rodon J, Serra V and Tabernero J. Picking the point of inhibition: A comparative review of PI3K/AKT/mTOR pathway inhibitors. Mol Cancer Ther 13: 1021-1031, 2014