Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review)
- Authors:
- George Mihai Nitulescu
- Denisa Margina
- Petras Juzenas
- Qian Peng
- Octavian Tudorel Olaru
- Emmanouil Saloustros
- Concettina Fenga
- Demetrios Α. Spandidos
- Massimo Libra
- Aristidis M. Tsatsakis
-
Affiliations: Faculty of Pharmacy, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest 020956, Romania, Department of Pathology, Radiumhospitalet, Oslo University Hospital, 0379 Oslo, Norway, Oncology Unit, General Hospital of Heraklion ‘Venizelio’, Heraklion 71409, Greece, Section of Occupational Medicine, University of Messina, I-98125 Messina, Italy, Department of Virology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece, Department of Biomedical and Biotechnological Sciences, General and Clinical Pathology and Oncology Section, University of Catania, I‑95124 Catania, Italy, Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece - Published online on: December 24, 2015 https://doi.org/10.3892/ijo.2015.3306
- Pages: 869-885
-
Copyright: © Nitulescu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
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|
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. View Article : Google Scholar | |
|
Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Arcaro A and Guerreiro AS: The phosphoinositide 3-kinase pathway in human cancer: Genetic alterations and therapeutic implications. Curr Genomics. 8:271–306. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Altomare DA and Testa JR: Perturbations of the AKT signaling pathway in human cancer. Oncogene. 24:7455–7464. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. | |
|
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. | |
|
Davis WJ, Lehmann PZ and Li W: Nuclear PI3K signaling in cell growth and tumorigenesis. Front Cell Dev Biol. 3:242015. View Article : Google Scholar : PubMed/NCBI | |
|
Sasaki T, Yamashita Y and Kuniyasu H: AKT plays a crucial role in gastric cancer (Review). Oncol Lett. 10:607–611. 2015.PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
Carnero A and Paramio JM: The PTEN/PI3K/AKT Pathway in vivo, Cancer Mouse Models. Front Oncol. 4:2522014. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Jhaveri K and Modi S: Ganetespib: Research and clinical development. Onco Targets Ther. 8:1849–1858. 2015.PubMed/NCBI | |
|
O‘Neill AK, Niederst MJ and Newton AC: Suppression of survival signalling pathways by the phosphatase PHLPP. FEBS J. 280:572–583. 2013. View Article : Google Scholar : | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Cohen MM Jr: The AKT genes and their roles in various disorders. Am J Med Genet A. 161A:2931–2937. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Emamian ES: AKT/GSK3 signaling pathway and schizophrenia. Front Mol Neurosci. 5:332012. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Osorio-Fuentealba C and Klip A: Dissecting signalling by individual Akt/PKB isoforms, three steps at once. Biochem J. 470:e13–e16. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
West KA, Castillo SS and Dennis PA: Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Updat. 5:234–248. 2002. View Article : Google Scholar | |
|
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.PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. | |
|
Carnero A: The PKB/AKT pathway in cancer. Curr Pharm Des. 16:34–44. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Olaru OT, Niţulescu GM, Orţan 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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Kumar CC and Madison V: AKT crystal structure and AKT-specific inhibitors. Oncogene. 24:7493–7501. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Böckmann S and Nebe B: The in vitro effects of H-89, a specific inhibitor of protein kinase A, in the human colonic carcinoma cell line Caco-2. Eur J Cancer Prev. 12:469–478. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Murray AJ: Pharmacological PKA inhibition: All may not be what it seems. Sci Signal. 1:re4-re42008. View Article : Google Scholar | |
|
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), a novel inhibitor of AKT kinase. J Med Chem. 51:5663–5679. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Yap TA, Walton MI, Hunter L-JK, 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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Crafter C, Vincent JP, Tang E, Dudley P, James NH, Klinowska T and Davies BR: Combining AZD8931, a novel 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.PubMed/NCBI | |
|
Lamoureux F and Zoubeidi A: Dual inhibition of autophagy and the AKT pathway in prostate cancer. Autophagy. 9:1119–1120. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 19:1760–1772. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
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:TPS11112015. | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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:e1008802014. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
Deng R, Yang F, Chang SH, Tang J, Qin J, Feng GK, Ding K and Zhu XF: DC120, a novel and potent inhibitor of AKT kinase, induces tumor cell apoptosis and suppresses tumor growth. Mol Pharmacol. 82:189–198. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Faiman B and Richards T: Innovative agents in multiple myeloma. J Adv Pract Oncol. 5:193–202. 2014.PubMed/NCBI | |
|
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:e129132010. View Article : Google Scholar : PubMed/NCBI | |
|
Lu S, Li S and Zhang J: Harnessing allostery: A novel approach to drug discovery. Med Res Rev. 34:1242–1285. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. 7:12014. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Meuillet EJ: Novel inhibitors of AKT: Assessment of a different approach targeting the pleckstrin homology domain. Curr Med Chem. 18:2727–2742. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Gills JJ and Dennis PA: Perifosine: Update on a novel Akt inhibitor. Curr Oncol Rep. 11:102–110. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
van Blitterswijk WJ and Verheij M: Anticancer mechanisms and clinical application of alkylphospholipids. Biochim Biophys Acta. 1831.663–674. 2013. | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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:e1182013. View Article : Google Scholar : PubMed/NCBI | |
|
de Pachioni JA, Magalhães JG, Lima EJC, de Bueno LM, 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. | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar | |
|
Clive S, Gardiner J and Leonard RCF: Miltefosine as a topical treatment for cutaneous metastases in breast carcinoma. Cancer Chemother Pharmacol Suppl. 44:2000. | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Orlowski RZ: Novel agents for multiple myeloma to overcome resistance in phase III clinical trials. Semin Oncol. 40:634–651. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
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. 4:462009. View Article : Google Scholar : | |
|
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. 1:62006. View Article : Google Scholar : PubMed/NCBI | |
|
Kaleağasıoğlu 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. | |
|
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. 5:1082010. View Article : Google Scholar : PubMed/NCBI | |
|
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.PubMed/NCBI | |
|
Aggarwal BB and Ichikawa H: Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 4:1201–1215. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
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, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo. Cancer Prev Res (Phila). 4:1842–1851. 2011. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar | |
|
Weng JR, Tsai CH, Omar HA, Sargeant AM, Wang D, Kulp SK, Shapiro CL and Chen CS: OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt-NF-kappaB pathway and stress response signaling. Carcinogenesis. 30:1702–1709. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Meuillet EJ, Zuohe S, Lemos R, Ihle N, Kingston J, Watkins R, Moses SA, Zhang S, Du-Cuny L and Herbst R: Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther. 9:706–717. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
Nitulescu GM, Draghici C, Olaru OT, Matei L, Ioana A, Dragu LD and Bleotu C: Synthesis and apoptotic activity of new pyrazole derivatives in cancer cell lines. Bioorg Med Chem. 23:5799–5808. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
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, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 64:4394–4399. 2004. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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.PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. 2011. View Article : Google Scholar | |
|
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:e01404792015. View Article : Google Scholar : PubMed/NCBI | |
|
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): 36852014. View Article : Google Scholar | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar | |
|
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. View Article : Google Scholar | |
|
Toral-Barza L, Zhang WG, Huang X, McDonald LA, Salaski EJ, 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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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:e30652008. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. View Article : Google Scholar : PubMed/NCBI | |
|
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. | |
|
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. View Article : Google Scholar | |
|
Banerji U, Ranson M, Schellens J, Schellens JH, Esaki T, Dean EJ 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. View Article : Google Scholar | |
|
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. View Article : Google Scholar : PubMed/NCBI |
