Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination

Proceedings of the National Academy of Sciences of the United States of America

Volumn 108, Issue 16, 2011, Pages 6486-6491

  Jo, Hakryul ^a   Lo, Pang Kuo ^b   Li, Yitang ^a   Loison, Fabien ^a   Green, Sarah ^a   Wang, Jake ^a   Silberstein, Leslie E ^a   Ye, Keqiang ^c   Chen, Hexin ^b   Luo, Hongbo R ^a  

^a DANA FARBER HARVARD CANCER CENTER   (United States)

^b UNIVERSITY OF SOUTH CAROLINA   (United States)

^c EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Cell death; Chemical screening

Indexed keywords

AGAR; ANTINEOPLASTIC AGENT; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE; PLECKSTRIN; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR;

ALLOSTERISM; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER INHIBITION; CELL GROWTH; CELL TRANSFORMATION; ENZYME INHIBITION; HUMAN; HUMAN CELL; MOUSE; MUTANT; NONHUMAN; PH; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DOMAIN; SEQUENCE HOMOLOGY; UBIQUITINATION; XENOGRAFT;

ALLOSTERIC REGULATION; AMINO ACID SUBSTITUTION; ANIMALS; ANTINEOPLASTIC AGENTS; FEMALE; HEK293 CELLS; HELA CELLS; HUMANS; MICE; MICE, INBRED NOD; MICE, SCID; MUTATION, MISSENSE; PHOSPHATIDYLINOSITOLS; PROTEIN BINDING; PROTEIN KINASE INHIBITORS; PROTEIN STRUCTURE, TERTIARY; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; UBIQUITINATION; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 79955572687     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1019062108     Document Type: Article

References (30)

1. Bunney TD, Katan M (2010) Phosphoinositide signalling in cancer: Beyond PI3K and PTEN. Nat Rev Cancer 10:342-352.
2. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606-619. (Pubitemid 44100518)
3. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9-22. (Pubitemid 47001784)
4. Bozulic L, Hemmings BA (2009) PIKKing on PKB: Regulation of PKB activity by phosphorylation. Curr Opin Cell Biol 21:256-261.
5. Engelman JA (2009) Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer 9:550-562.
6. Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511-5526.
7. Knight ZA, Shokat KM (2007) Chemically targeting the PI3K family. Biochem Soc Trans 35:245-249. (Pubitemid 46596480)
8. Zunder ER, Knight ZA, Houseman BT, Apsel B, Shokat KM (2008) Discovery of drug-resistant and drug-sensitizing mutations in the oncogenic PI3K isoform p110 alpha. Cancer Cell 14:180-192.
9. Alaimo PJ, Knight ZA, Shokat KM (2005) Targeting the gatekeeper residue in phosphoinositide 3-kinases. Bioorg Med Chem 13:2825-2836. (Pubitemid 40387492)
10. Apsel B, et al. (2008) Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol 4:691-699.
11. Chen J, Tang H, Hay N, Xu J, Ye RD (2010) Akt isoforms differentially regulate neutrophil functions. Blood 115:4237-4246.
12. Luo HR, et al. (2003) Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions. Cell 114:559-572.
13. Jia Y, et al. (2007) Inositol 1,3,4,5-tetrakisphosphate negatively regulates PtdIns(3,4,5) P3 signaling in neutrophils. Immunity 27:453-467.
14. Yang WL, et al. (2009) The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325:1134-1138.
15. Suizu F, et al. (2009) The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt. Dev Cell 17:800-810.
16. Toker A (2009) TTC3 ubiquitination terminates Akt-ivation. Dev Cell 17:752-754.
17. Hartnett JC, et al. (2008) Optimization of 2,3,5-trisubstituted pyridine derivatives as potent allosteric Akt1 and Akt2 inhibitors. Bioorg Med Chem Lett 18:2194-2197. (Pubitemid 351380851)
18. Ajmani S, Agrawal A, Kulkarni SA (2010) A comprehensive structure-activity analysis of protein kinase B-alpha (Akt1) inhibitors. J Mol Graph Model 28:683-694.
19. Fei ZL, D'Ambrosio C, Li S, Surmacz E, Baserga R (1995) Association of insulin receptor substrate 1 with simian virus 40 large T antigen. Mol Cell Biol 15:4232-4239.
20. Kau TR, et al. (2003) A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 4:463-476. (Pubitemid 38050043)
21. Badano JL, Teslovich TM, Katsanis N (2005) The centrosome in human genetic disease. Nat Rev Genet 6:194-205. (Pubitemid 40293030)
22. Barnett SF, et al. (2005) Identification and characterization of pleckstrin-homology-domain- dependent and isoenzyme-specific Akt inhibitors. Biochem J 385:399-408. (Pubitemid 40165072)
23. Carpten JD, et al. (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439-444. (Pubitemid 47123510)
24. Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL (2008) Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27:1919-1931.
25. Facchinetti V, et al. (2008) The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27:1932-1943.
26. Luo HR, et al. (2003) Akt as a mediator of cell death. Proc Natl Acad Sci USA 100:11712-11717. (Pubitemid 37206000)
27. Manning BD, Cantley LC (2007) AKT/PKB signaling: Navigating downstream. Cell 129:1261-1274. (Pubitemid 46962095)
28. Jo H, et al. (2010) Natural product Celastrol destabilizes tubulin heterodimer and facilitates mitotic cell death triggered by microtubule- targeting anti-cancer drugs. PLoS ONE 5:e10318.
29. Yang L, et al. (2004) 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. (Pubitemid 38856907)
30. Jo H, Jia Y, Subramanian KK, Hattori H, Luo HR (2008) Cancer cell-derived clusterin modulates the phosphatidylinositol 3′-kinase-Akt pathway through attenuation of insulin-like growth factor 1 during serum deprivation. Mol Cell Biol 28:4285-4299. (Pubitemid 351904951)