Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity

Cancer Research

Volumn 73, Issue 6, 2013, Pages 1993-2002

  Atkins, Charity ^a   Liu, Qi ^a   Minthorn, Elisabeth ^a   Zhang, Shu Yun ^a   Figueroa, David J ^a   Moss, Katherine ^a   Stanley, Thomas B ^c   Sanders, Brent ^a   Goetz, Aaron ^b   Gaul, Nathan ^b   Choudhry, Anthony E ^b   Alsaid, Hasan ^d   Jucker, Beat M ^d   Axten, Jeffrey M ^a   Kumar, Rakesh ^a  

^a GLAXOSMITHKLINE   (United States)

^b Platform Technology and Science   (United States)

^c Platform Technology and Science   (United States)

^d Preclinical and Translational Imaging LAS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATING TRANSCRIPTION FACTOR 4; ANGIOGENESIS INHIBITOR; ANTINEOPLASTIC AGENT; CCAAT ENHANCER BINDING PROTEIN; EUKARYOTIC INITIATION FACTOR 2 ALPHA KINASE 3 INHIBITOR; GSK 2656157; INITIATION FACTOR 2ALPHA KINASE 3; PROTEIN KINASE R; UNCLASSIFIED DRUG;

AMINO ACID METABOLISM; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIANGIOGENIC ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTICLE; AUTOPHOSPHORYLATION; BLOOD VESSEL PARAMETERS; CANCER INHIBITION; CELL STRESS; CONTROLLED STUDY; DOSE RESPONSE; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG STRUCTURE; DRUG TISSUE LEVEL; ENZYME ACTIVITY; ENZYME SUBSTRATE; FEMALE; HISTOPATHOLOGY; HUMAN; HUMAN CELL; IC 50; MOUSE; NONHUMAN; PANCREAS CANCER; PANCREAS FUNCTION; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; UNFOLDED PROTEIN RESPONSE;

ANGIOGENESIS INHIBITORS; ANIMALS; ANTINEOPLASTIC AGENTS; EIF-2 KINASE; FEMALE; GENE EXPRESSION PROFILING; MICE; PROTEIN KINASE INHIBITORS;

EID: 84875235453     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-12-3109     Document Type: Article

References (38)

1. Koumenis C, Wouters BG. "Translating" tumor hypoxia: unfolded protein response (UPR)-dependent and UPR-independent pathways. Mol Cancer Res 2006;4:423-36.
2. Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 2004;4: 966-77.
3. Feldman DE, Chauhan V, Koong AC. The unfolded protein response: a novel component of the hypoxic stress response in tumors. Mol Cancer Res 2005;3:597-605.
4. Hamanaka RB, Bobrovnikova-Marjon E, Ji X, Liebhaber SA, Diehl JA. PERK-dependent regulation of IAP translation during ER stress. Oncogene 2009;28:910-20.
5. Ma Y, Hendershot LM. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell Stress Chaperones 2002;7:222-9.
6. Shi Y, Vattem KM, Sood R, An J, Liang J, Stramm L, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2a-subunit kinase, PEK, involved in translational control. Mol Cell Biol 1998;18:7499-509.
7. Sood R, Porter AC, Olsen DA, Cavener DR, Wek RC. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2a. Genetics 2000;154:787-801.
8. Ma Y, Lu Y, Zeng H, Ron D, Mo W, Neubert TA. Characterization of phosphopeptides from protein digests using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and nanoelectrospray quadrupole time-of-flight mass spectrometry. Rapid Commun Mass Spectrom 2001;15:1693-700.
9. Su Q, Wang S, Gao HQ, Kazemi S, Harding HP, Ron D, et al. Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem 2008;283:469-75.
10. Marciniak SJ, Garcia-Bonilla L, Junjie Hu J, Harding HP, Ron D. Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol 2006;172:201-9.
11. Cullinan SB, Diehl JA. PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following ERstress. J BiolChem 2004;279:20076-87.
12. -/- mice reveals a role for translational control in survival of secretory cells. Mol Cell 2001;7:1153-63.
13. Zhang W, Feng D, Li Y, Iida K, McGrath B, Cavener DR. PERK EIF2AK3 control of pancreatic b cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metabol 2006;4:491-7.
14. Iida K, Li Y,McGrath BC, Frank A, Cavener DR. PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol 2007;8:1-16.
15. Senee V, VattemKM, Delepine M, Rainbow LA, Haton C, Lecoq A, et al. Wolcott-Rallison syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 2004;53:1876-83.
16. Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare Dis 2010;5:1-13.
17. Gupta S,McGrath B, Cavener DR.PERK regulates the proliferation and development of insulin-secreting beta-cell tumors in the endocrine pancreas of mice. PLoS ONE 2009;4:1-6.
18. Cavener DR, Gupta S, McGrath BC. PERK in beta cell biology and insulin biogenesis. Trends Endocrinol Metabol 2010;21:714-21.
19. Gupta S, McGrath B, Cavener DR. PERK (EIF2AK3) regulates proinsulin tranfficking and quality control in the secretory pathway. Diabetes 2010;59:1937-47.
20. Wei J, Sheng X, Feng D, McGrath B, Cavener DR. PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol 2008;217:693-707.
21. Bi M, Naczki C, Koritzinsky M, Fels D, Blais J, Hu N, et al. ER stressregulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J 2005;24:3470-81.
22. Brown J,Giaccia A. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998;58:1408-16.
23. Blais JD, Addison CL, Edge R, Falls T, Zhao H, Wary K, et al. Perkdependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol 2006;26: 9517-32.
24. Koumenis C, Naczki C, Koritzinsky M, Rastani S, Diehl A, Sonenberg N, et al. Regulation of protein synthesis by hypoxia via activation of the endoplasmic reticulum kinase PERK and phosphorylation of the translation initiation factor eIF2a. Mol Cell Biol 2002;22:7405-16.
25. Romero-Ramirez LH, Cao H, Nelson D, Hammond E, Lee AH, Yoshida H, et al. XBP1 is essential for survival under hypoxic conditions and is required for tumor growth. Cancer Res 2004;64:5943-7.
26. Ghosh R, Lipson KL, Sargent KE, Mercurio AM, Hunt JS, Ron D, et al. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS ONE 2010;5:1-12.
27. Jorgensen E, Stinson A, Shan L, Yang J, Gietl D, Albino AP. Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells. BMC Cancer 2008;8:1-30.
28. Ameri K, Lewis CE, Raida M, Sowter H, Hai T, Harris AL. Anoxic induction of ATF-4 through HIF-1-independent pathways of protein stabilization in human cancer cells. Blood 2004;103:1876-82.
29. Davies MPA, Barraclough DL, Stewart C, Joyce KA, Eccles RM, Barraclough R, et al. Expression and splicing of the unfolded protein response gene XBP-1 are significantly associated with clinical outcome of endocrine-treated breast cancer. Int J Cancer 2008;123:85-8.
30. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Seth WG, et al. Discovery of 7-methyl-5-(1-{[3- (trifluoromethyl)phenyl]acetyl}-2, 3-dihydro-1H-indol-5- yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of PKR-like endoplasmic reticulum kinase (PERK). J Med Chem 2012; 55:7193-207.
31. Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, et al. The PERK eukaryotic initiation factor 2a kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 2002;22:3864-74.
32. Teske BF, Baird TD, Wek RC. Methods for analyzing eIF2 kinases and translational control in the unfolded protein response. Methods Enzymol 2011;490:333-56.
33. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999;397:271-4.
34. Gales T, Ringenberg M, Mirabile R, Kane J, Hart T, Laffan S, et al. PERK inhibitor induces pancreatic toxicity in rats. Soc Tox Path 2012, Abs#87.
35. Lee A-H, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 2003;23:7448-59.
36. Gjymishka A, Su N, Kilberg MS. Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway. Biochem J 2009;417:695-703.
37. Bull VH, Thlede B. Proteome analysis of tunicamycin-induced ER stress. Electrophoresis 2012;33:1814-23.
38. Drogat B, Auguste P, Nguyen DT, Bouchecareilh M, Pineau R, Nalbantoglu I, et al. IRE1 signaling is essential for ischemiainduced vascular endothelial growth factor-a expression and contributes to angiogenesis and tumor growth in vivo. Cancer Res 2007;67:6700-7.