Protein kinase R(PKR)–like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015)

Expert Opinion on Therapeutic Patents

Volumn 27, Issue 1, 2017, Pages 37-48

  Axten, Jeffrey M ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

Cancer; ER stress; kinase; neurodegeneration; PERK; protein synthesis; unfolded protein response

Indexed keywords

PROTEIN INHIBITOR; PROTEIN KINASE R; PERK KINASE; PROTEIN KINASE INHIBITOR;

ENDOPLASMIC RETICULUM; GENETIC TRANSCRIPTION; MODULATION; PATENT; PHENOTYPE; PROTEIN SYNTHESIS; REVIEW; UNFOLDED PROTEIN RESPONSE; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DESIGN; DRUG EFFECTS; ENDOPLASMIC RETICULUM STRESS; HUMAN; NEOPLASMS; NEURODEGENERATIVE DISEASES; PATHOLOGY; PATHOPHYSIOLOGY;

ANIMALS; DRUG DESIGN; EIF-2 KINASE; ENDOPLASMIC RETICULUM STRESS; HUMANS; NEOPLASMS; NEURODEGENERATIVE DISEASES; PATENTS AS TOPIC; PROTEIN KINASE INHIBITORS; UNFOLDED PROTEIN RESPONSE;

EID: 85003811106     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1080/13543776.2017.1238072     Document Type: Review

References (109)

1. Ellgaard L, Helenius A., Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2003;4(3):181–191.• This is a comprehensive review of protein folding and processing in the ER.
2. Cao SS, Kaufman RJ. Unfolded protein response. Curr Biol. 2012;22(16):R622–R626.
3. Jager R, Bertrand MJ, Gorman AM, et al. The unfolded protein response at the crossroads of cellular life and death during endoplasmic reticulum stress. Biol Cell. 2012;104(5):259–270.
4. Hetz C. The unfolded protein response:controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.
5. Walter P, Ron D. The unfolded protein response:from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081–1086.•• This article provides a review of the fundamental basis of the UPR and management of ER homeostasis.
6. Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2(6):326–332.
7. Gardner BM, Pincus D, Gotthardt K, et al. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol. 2013;5(3):a013169.
8. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397(6716):271–274.• This is an original article on the isolation and characterization of PERK.
9. Shi Y, Vattem KM, Sood R, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998;18(12):7499–7509.• This article was the first report identifying PERK.
10. Sood R, Porter AC, Ma K, et al. Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. Biochem J. 2000;346(Pt 2):281–293.
11. Ma Y, Lu Y, Zeng H, et al. 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(18):1693–1700.
12. Su Q, Wang S, Gao HQ, et al. Modulation of the eukaryotic initiation factor 2 alpha-subunit kinase PERK by tyrosine phosphorylation. J Biol Chem. 2008;283(1):469–475.
13. Marciniak SJ, Garcia-Bonilla L, Hu J, et al. Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol. 2006;172(2):201–209.
14. Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415(6867):92–96.
15. Zhou J, Liu CY, Back SH, et al. The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Proc Natl Acad Sci U S A. 2006;103(39):14343–14348.
16. Yoshida H, Haze K, Yanagi H, et al. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem. 1998;273(50):33741–33749.
17. Wang Y, Shen J, Arenzana N, et al. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem. 2000;275(35):27013–27020.
18. Zhang P, McGrath B, Li S, et al. The PERK eukaryotic initiation factor 2 alpha 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(11):3864–3874.
19. Zhang W, Feng D, Li Y, et al. PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab. 2006;4(6):491–497.
20. −/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7(6):1153–1163.
21. Iida K, Li Y, McGrath BC, et al. PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol. 2007;8:38.
22. Gupta S, McGrath B, Cavener DR. PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes. 2010;59(8):1937–1947.
23. Cavener DR, Gupta S, McGrath BC. PERK in beta cell biology and insulin biogenesis. Trends Endocrinol Metab. 2010;21(12):714–721.•• This is an excellent review of PERK-dependent β-cell biology.
24. Harding HP, Zyryanova AF, Ron D. Uncoupling proteostasis and development in vitro with a small molecule inhibitor of the pancreatic endoplasmic reticulum kinase, PERK. J Biol Chem. 2012;287(53):44338–44344.
25. Yu Q, Zhao B, Gui J, et al. Type I interferons mediate pancreatic toxicities of PERK inhibition. Proc Natl Acad Sci U S A. 2015;112(50):15420–15425.
26. Suk K, Kim S, Kim YH, et al. IFN-gamma/TNF-alpha synergism as the final effector in autoimmune diabetes:a key role for STAT1/IFN regulatory factor-1 pathway in pancreatic beta cell death. J Immunol. 2001;166(7):4481–4489.
27. Lin W, Harding HP, Ron D, et al. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol. 2005;169(4):603–612.
28. Delepine M, Nicolino M, Barrett T, et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet. 2000;25(4):406–409.
29. Senee V, Vattem KM, Delepine M, et al. Wolcott-Rallison Syndrome:clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes. 2004;53(7):1876–1883.
30. Julier C, Nicolino M. Wolcott-Rallison syndrome. Orphanet J Rare Dis. 2010;5:29.•• This review provides background and summarizes collective data on cases of WRS, the human condition characterized by inactivating PERK mutations.
31. Bruch J, Kurz C, Vasiljevic A, et al. Early neurodegeneration in the brain of a child without functional PKR-like endoplasmic reticulum kinase. J Neuropathol Exp Neurol. 2015;74(8):850–857.
32. Trinh MA, Kaphzan H, Wek RC, et al. Brain-specific disruption of the eIF2alpha kinase PERK decreases ATF4 expression and impairs behavioral flexibility. Cell Rep. 2012;1(6):676–688.
33. Wek RC, Cavener DR. Translational control and the unfolded protein response. Antioxid Redox Signal. 2007;9(12):2357–2371.
34. Pavitt GD, Ron D. New insights into translational regulation in the endoplasmic reticulum unfolded protein response. Cold Spring Harb Perspect Biol. 2012;4:6.
35. Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110(10):1383–1388.
36. Harding HP, Novoa I, Bertolotti A, et al. Translational regulation in the cellular response to biosynthetic load on the endoplasmic reticulum. Cold Spring Harb Symp Quant Biol. 2001;66:499–508.
37. Harding HP, Novoa I, Zhang Y, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–1108.
38. Wortham NC, Proud CG. eIF2B:recent structural and functional insights into a key regulator of translation. Biochem Soc Trans. 2015;43(6):1234–1240.
39. Ramaiah KV, Davies MV, Chen JJ, et al. Expression of mutant eukaryotic initiation factor 2 alpha subunit (eIF-2 alpha) reduces inhibition of guanine nucleotide exchange activity of eIF-2B mediated by eIF-2 alpha phosphorylation. Mol Cell Biol. 1994;14(7):4546–4553.
40. Spriggs KA, Bushell M, Willis AE. Translational regulation of gene expression during conditions of cell stress. Mol Cell. 2010;40(2):228–237.
41. Blais JD, Filipenko V, Bi M, et al. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol. 2004;24(17):7469–7482.
42. Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci U S A. 2004;101(31):11269–11274.
43. Starck SR, Tsai JC, Chen K, et al. Translation from the 5ʹ untranslated region shapes the integrated stress response. Science. 2016;351(6272):aad3867.
44. Ohoka N, Yoshii S, Hattori T, et al. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. EMBO J. 2005;24(6):1243–1255.
45. Lange PS, Chavez JC, Pinto JT, et al. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med. 2008;205(5):1227–1242.• This article studies the stress-dependent knock out of ATF4 in neurons and evaluates corresponding changes in gene expression.
46. Novoa I, Zhang Y, Zeng H, et al. Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 2003;22(5):1180–1187.
47. Donnelly N, Gorman AM, Gupta S, et al. The eIF2alpha kinases:their structures and functions. Cell Mol Life Sci. 2013;70(19):3493–3511.
48. Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. Physiol Rev. 2006;86(4):1133–1149.• This article reviews potential therapeutic uses of PERK inhibitors.
49. Zhang K, Kaufman RJ. The unfolded protein response:a stress signaling pathway critical for health and disease. Neurology. 2006;66(2 Suppl 1):S102–S109.• This article reviews potential therapeutic uses of PERK inhibitors.
50. Hiramatsu N, Chiang WC, Kurt TD, et al. Multiple mechanisms of unfolded protein response-induced cell death. Am J Pathol. 2015;185(7):1800–1808.
51. Maly DJ, Papa FR. Druggable sensors of the unfolded protein response. Nat Chem Biol. 2014;10(11):892–901.
52. Han J, Back SH, Hur J, et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol. 2013;15(5):481–490.
53. Lu PD, Jousse C, Marciniak SJ, et al. Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J. 2004;23(1):169–179.
54. Lin Y, Pang X, Huang G, et al. Impaired eukaryotic translation initiation factor 2B activity specifically in oligodendrocytes reproduces the pathology of vanishing white matter disease in mice. J Neurosci. 2014;34(36):12182–12191.
55. Ranganathan AC, Ojha S, Kourtidis A, et al. Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. Cancer Res. 2008;68(9):3260–3268.
56. Stockwell SR, Platt G, Barrie SE, et al. Mechanism-based screen for G1/S checkpoint activators identifies a selective activator of EIF2AK3/PERK signalling. PLoS One. 2012;7(1):e28568.
57. Xie W, Pariollaud M, Wixted WE, et al. Identification and characterization of PERK activators by phenotypic screening and their effects on NRF2 activation. PLoS One. 2015;10(3):e0119738.
58. Deutsches Zentrum fuer Neurodegenerative Erkrankungen e.V. DZNE. PERK activator for the treatment of neurodegenerative diseases patent. WO2016024010. 2016.
59. Wang L, Popko B, Tixier E, et al. Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis. Neurobiol Dis. 2014;71:317–324.
60. Way SW, Popko B. Harnessing the integrated stress response for the treatment of multiple sclerosis. Lancet Neurol. 2016;15(4):434–443.
61. Tribouillard-Tanvier D, Beringue V, Desban N, et al. Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions. PLoS One. 2008;3(4):e1981.
62. Vieira FG, Ping Q, Moreno AJ, et al. Guanabenz treatment accelerates disease in a mutant SOD1 mouse model of ALS. PLoS One. 2015;10(8):e0135570.
63. Bi M, Naczki C, Koritzinsky M, et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 2005;24(19):3470–3481.
64. Axten JM, Medina JR, Feng Y, et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem. 2012;55(16):7193–7207.•• An account of the medicinal chemistry optimization leading to the discovery of GSK2606414.
65. Axten JM, Romeril SP, Shu A, et al. Discovery of GSK2656157:an optimized PERK inhibitor selected for preclinical development. ACS Med Chem Lett. 2013;4(10):964–968.•• An account of the medicinal chemistry optimization leading to the discovery of GSK2656157.
66. Fribley AM, Cruz PG, Miller JR, et al. Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response. J Biomol Screen. 2011;16(8):825–835.
67. Wang H, Blais J, Ron D, et al. Structural determinants of PERK inhibitor potency and selectivity. Chem Biol Drug Des. 2010;76(6):480–495.
68. Smith AL, Andrews KL, Beckmann H, et al. Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK). J Med Chem. 2015 Feb 12;58(3):1426–1441.• This article describes 1H-pyrazol-3(2H)-ones as another series of PERK inhibitors with anti-angiogenic activity from Amgen, and discloses a more selective analog of GSK2606414.
69. Vandewynckel YP, Laukens D, Bogaerts E, et al. Modulation of the unfolded protein response impedes tumor cell adaptation to proteotoxic stress:a PERK for hepatocellular carcinoma therapy. Hepatol Int. 2015;9(1):93–104.
70. Ma Y, Hendershot LM. The role of the unfolded protein response in tumour development:friend or foe? Nat Rev Cancer. 2004;4(12):966–977.
71. Maas NL, Diehl JA. Molecular pathways:the PERKs and pitfalls of targeting the unfolded protein response in cancer. Clin Cancer Res. 2015;21(4):675–679.
72. Pytel D, Majsterek I, Diehl JA. Tumor progression and the different faces of the PERK kinase. Oncogene. 2016;35(10):1207–1215.
73. Moreno JA, Halliday M, Molloy C, et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med. 2013;5(206):206ra138.•• This landmark paper demonstrated that a PERK inhibitor was neuroprotective and preserved behavior in a mouse model of prion-mediated neurodegeneration.
74. Kim HJ, Raphael AR, LaDow ES, et al. Therapeutic modulation of eIF2alpha phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet. 2014;46(2):152–160.
75. van der Harg JM, Nolle A, Zwart R, et al. The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress. Cell Death Dis. 2014;5:e1393.
76. Radford H, Moreno JA, Verity N, et al. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 2015;130(5):633–642.• This article reported efficacy of GSK2606414 in a dementia model, and showed that small molecule PERK inhibition can decrease tau phosphorylation.
77. Abisambra JF, Jinwal UK, Blair LJ, et al. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci. 2013;33(22):9498–9507.
78. Nijholt DA, van Haastert ES, Rozemuller AJ, et al. The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol. 2012;226(5):693–702.
79. Baek J-H, Whitfield D, Howlett D, et al. Unfolded protein response is activated in Lewy body dementias. Neuropathol Appl Neurobiol. 2016;42:352–365.
80. Stutzbach LD, Xie SX, Naj AC, et al. The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Commun. 2013;1:31.• This article reveals genetic evidence of PERK activation in PSP.
81. Hoozemans JJ, van Haastert ES, Nijholt DA, et al. The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol. 2009;174(4):1241–1251.
82. Hoozemans JJ, van Haastert ES, Eikelenboom P, et al. Activation of the unfolded protein response in Parkinson’s disease. Biochem Biophys Res Commun. 2007;354(3):707–711.
83. van der Voorn JP, van Kollenburg B, Bertrand G, et al. The unfolded protein response in vanishing white matter disease. J Neuropathol Exp Neurol. 2005;64(9):770–775.
84. Hoozemans JJ, Veerhuis R, van Haastert ES, et al. The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol. 2005;110(2):165–172.
85. Atkin JD, Farg MA, Walker AK, et al. Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol Dis. 2008;30(3):400–407.
86. Scheper W, Hoozemans JJ. The unfolded protein response in neurodegenerative diseases:a neuropathological perspective. Acta Neuropathol. 2015;130(3):315–331.•• An excellent review of the human evidence of PERK activation in neurodegenerative disease.
87. Kim R, Emi M, Tanabe K, et al. Role of the unfolded protein response in cell death. Apoptosis. 2006;11(1):5–13.
88. Blais JD, Addison CL, Edge R, et al. Perk-dependent translational regulation promotes tumor cell adaptation and angiogenesis in response to hypoxic stress. Mol Cell Biol. 2006;26(24):9517–9532.
89. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer. 2014;14(9):581–597.•• This article provides comprehensive background and in depth perspective on ER stress and tumorigenesis.
90. Wang Y, Alam GN, Ning Y, et al. The unfolded protein response induces the angiogenic switch in human tumor cells through the PERK/ATF4 pathway. Cancer Res. 2012;72(20):5396–5406.
91. Carrara M, Prischi F, Nowak PR, et al. Crystal structures reveal transient PERK luminal domain tetramerization in endoplasmic reticulum stress signaling. EMBO J. 2015;34(11):1589–1600.
92. GlaxoSmithKline LLC. Preparation of substituted indoline derivatives as PKR-like ER kinase inhibitors patent. WO2011119663. 2011.•• This patent discloses a novel series of indoline derivatives as the first potent and selective inhibitors of PERK.
93. Atkins C, Liu Q, Minthorn E, et al. Characterization of a novel PERK kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res. 2013;73(6):1993–2002.•• This article contains the full biological characterization of GSK2656157, including in vivo efficacy and pharmacodynamics.
94. GlaxoSmithKline Intellectual Property No.2 Limited. Preparation of phenylpyrrolidinone derivatives for use as PERK inhibitors patent. WO2015136463. 2015.
95. Nerviano Medical Sciences S.r.l. Preparation of isoxazolo-quinazolines as modulators of protein kinase activity for treatment of proliferative disorders patent. WO2012013557. 2012.
96. Janssen Pharmaceutica NV. Preparation of novel N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-4-quinazolinamine and N-(2,3-dihydro-1H-indol-5-yl)-4-quinazolinamine derivatives as PERK inhibitors patent. WO2014161808. 2014.•• This patent discloses aminoquinazoline-substituted indolines as potent and selective PERK inhibitors.
97. Ron D, Harding HP. Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol. 2012;4(12):a013177.• This article gives a holistic view of the physiological basis for UPR evolution and development.
98. Halliday M, Mallucci GR. Review:modulating the unfolded protein response to prevent neurodegeneration and enhance memory. Neuropathol Appl Neurobiol. 2015;41(4):414–427.•• This is an excellent review of current data supporting the targeting of the UPR and PERK as an approach to treat neurodegenerative diseases.
99. Prusiner SB. Cell biology. A unifying role for prions in neurodegenerative diseases. Science. 2012;336(6088):1511–1513.•• This paper proposes a general theory that neurodegenerative diseases may have a common prion-independent mechanism of pathogenesis.
100. Halliday M, Radford H, Sekine Y, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 2015;6:e1672.• This study demonstrated that pharmacological restoration of protein synthesis at a pathway node downstream of PERK was efficacious in a model of prion diseases.
101. Sidrauski C, Acosta-Alvear D, Khoutorsky A, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife. 2013;2:e00498.
102. Sekine Y, Zyryanova A, Crespillo-Casado A, et al. Stress responses. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science. 2015;348(6238):1027–1030.
103. Sidrauski C, Tsai JC, Kampmann M, et al. Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife. 2015;4:e07314.
104. Picchioni D, Reith RM, Nadel JL, et al. Sleep, plasticity and the pathophysiology of neurodevelopmental disorders:the potential roles of protein synthesis and other cellular processes. Brain Sci. 2014;4(1):150–201.• This article reviews the critical need to maintain protein synthesis for sleep as well as neurological and cognitive function.
105. Thomas SE, Dalton LE, Daly ML, et al. Diabetes as a disease of endoplasmic reticulum stress. Diabetes Metab Res Rev. 2010;26(8):611–621.
106. Ma JH, Wang JJ, Zhang SX. The unfolded protein response and diabetic retinopathy. J Diabetes Res. 2014;2014:160140.
107. Volmer R, van der Ploeg K, Ron D. Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains. Proc Natl Acad Sci U S A. 2013;110(12):4628–4633.
108. Herbert TP, Laybutt DR. A reevaluation of the role of the unfolded protein response in islet dysfunction:maladaptation or a failure to adapt? Diabetes. 2016;65(6):1472–1480.•• This article presents the diverse effects of ER stress on islets with relevance to modulation of PERK.
109. Abdulkarim B, Nicolino M, Igoillo-Esteve M, et al. A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Diabetes. 2015;64(11):3951–3962.