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Protein Kinase and Protein Tyrosine Kinase Inhibitors
2-Aminopurine - PKR Inhibitor
2-aminopurine (2-AP) is a potent inhibitor of double-stranded RNA (dsRNA)-activated protein kinase (PKR), a critical mediator of apoptosis. PKR is
phosphorylated and activated by dsRNA and poly(I:C) 1 and contributes to the induction of type I interferons, such as IFN-b, which can further increase its
expression 2 . PKR plays also a role in TLR-induced antiviral activities as an intermediary in TLR3, TLR4 and TLR9 signaling 3 .
AG490 - JAK2 Inhibitor
AG490 is a specific and potent inhibitor of the Janus kinase 2 protein (JAK2) 4 AG490 is used to inhibit phosphorylation of the tyrosine kinase receptor EGFR
and signal transducer and activator of transcription 3 (STAT-3), and subsequently reduce invasion and adhesion potential of malignant cells 5 .
H-89 - PKA Inhibitor
H-89 is a selective, potent cell permeable inhibitor of cAMP-dependent protein kinase (PKA) 6 . It can be used to determine the role of PKA in TLR and other
PRR mediated signaling. PKA has be shown to participate in the TLR-mediated TREM-1 expression on macrophages following LPS stimulation ,7 .
1. Kaufman RJ., 1999. Double-stranded RNA-activated protein kinase mediated virus-induced apoptosis: a new role for an old actor. Proc. Natl. Acad. Sci. USA 96 (21):11693-5. 2. Samuel
CE., 2001. Antiviral actions of interferons. Clin Microbiol Rev. 14(4):778-809. 3. García MA. et al., 2006. Impact of Protein Kinase PKR in Cell Biology: from Antiviral to Antiproliferative
Action,Microbiol. Mol. Biol. Rev., 70: 1032 - 1060. 4. Levitzki A., 1990. Tyrphostins- potential antiprolierative agents and novel molecular tools. Biochem. Pharmacol. 40:913-918. 5. Caceres-
Cortes JR., 2008. A potent anti-carcinoma and anti-acute myeloblastic leukemia agent, AG490. Anticancer Agents Med Chem. 8(7):717-22. 6. Chijiwa, T., et al.,1990. Inhibition of forskolininduced
neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)
ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J. Biol. Chem. 265: 5267-5272. 7. Murakami Y. et al., 2007. Lipopolysaccharide-Induced Up-Regulation of Triggering
Receptor Expressed on Myeloid Cells-1 Expression on Macrophages Is Regulated by Endogenous Prostaglandin E2. J. Immunol. 178: 44. 2
Epigenetic Inhibitors
5-Aza-cytidine - DNA Methyltransferase Inhibitor
5-aza-cytidine (AZA) is a potent inhibitor of DNA methyltransferase 1 (DNMT1), known to induce demethylation and reactivation of silenced genes. In a
recent article, reactivation of hypermethylated pluripotency genes was suggested to be important for complete reprogramming. Consistent with this notion,
AZA was shown to facilitate the transition to full pluripotency of partially reprogrammed cell line and to increase the number of ES cell-like colonies 1 .
Hangfu et al. confirmed that AZA treatment promotes reprogramming efficiency 2 .
5-Aza-2’-deoxycytidine - DNA Methyltransferase Inhibitor
5-Aza-2’-deoxycytidine (5-AzadCyD, 5-Aza-CdR, decitabine) is a specific inhibitor of DNA methylation. It functions in a similar manner to aza-citidine, although
decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains. 5-AzadCyD is a prodrug that
requires activation via phosphorylation by deoxycytidine kinase. The nucleotide analog is incorporated into DNA, where it produces an irreversible inactivation
of DNA methyltransferase. 5-AzadCyD was demonstrated to be a potent antineoplastic agent against leukemia and tumors in animal models 3, 4 .
Bix-01294 - G9a Histone Methyltransferase Inhibitor
Bix-01294 is an inhibitor of the G9a histone methyltransferase, a key regulator of DNA methylation and transcriptional silencing in pluripotent cells 5 . Bix-
01294 is believed to facilitate the reactivation of pluripotency genes and induce passive demethylation, thus promoting reprogramming. Indeed, Bix-01294
was found to improve reprogramming efficiencies of Oct4-Klf4-(OK)-infected neural progenitor cells by approximately 8 fold 6 .
Trichostatin A - Histone deacetylase Inhibitor
Trichostatin A (TSA) is a potent and specific inhibitor of histone deacetylase (HDAC). TSA suppresses the activity of HDAC leading to an increase in histone
acetylation. TSA has been shown to induce apoptosis in many cancer cells at submicromolar concentrations with very low toxicity toward normal cells 7 .
Furthermore, TSA is used to improve the genomic reprogramming of embryos generated by somatic cell nuclear transfer 8 .
Valproic acid - Histone deacetylase Inhibitor
Valproic acid (VPA) is a histone deacetylase inhibitor with potent antitumor activity 9 . VPA treatment promotes histone acetylation allowing the chromatin to
adopt a relaxed structure facilitating the binding of ectopically expressed transcription factors or downstream secondary factors. VPA was found to significantly
enhance reprogramming efficiencies of OSKM-, OSK- and OS-infected fibroblasts, eliminating the need for the oncogenes c-Myc or Klf4 2, 10 . VPA is believed
to induce global transcriptional changes, in particular upregulating ES cell-specific genes while downregulating MEF-specific genes.
1. Mikkelsen TS. et al., 2008. Dissecting direct reprogramming through integrative genomic analysis. Nature. 454(7200):49-55. 2. Huangfu D. et al., 2008a. Induction of pluripotent
stem cells by defined factors is greatly improved by small-molecule compounds. Nat Biotechnol. 26(7):795-7. 3. Christman JK., 2002. 5-Azacytidine and 5-aza-20-deoxycytidine
as inhibitors of DNA methylation: Mechanistic studies and their implications for cancer therapy. Oncogene 21, 5483–5495. 4. Kulis M. & Esteller M., 2010. DNA methylation and
cancer. Adv Genet. 2010;70:27-56. 5. Epsztejn-Litman S. et al., 2008. De novo DNA methylation promoted by G9a prevents reprogramming of embryonically silenced genes.
Nat Struct Mol Biol. 15(11):1176-83. 6. Shi Y et al., 2008. A combined chemical and genetic approach for the generation of induced pluripotent stem cells. Cell Stem Cell.
2(6):525-8. 7. David M. et al., 2001. Trichostatin A Is a Histone Deacetylase Inhibitor with Potent Antitumor Activity against Breast Cancer in Vivo. Clin. Cancer Res., Apr 2001;
7: 971 - 976. 8. Bui H-T, et al., 2010. Effect of Trichostatin A on Chromatin Remodeling, Histone Modifications, DNA Replication, and Transcriptional Activity in Cloned Mouse
Embryos. Biol Reprod, 83: 454 - 463. 9. Duenas-Gonzalez A. et al., 2008. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors.
Cancer Treat Rev. 34(3):206-22. 10 . Huangfu D. et al., 2008b. Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nat Biotechnol.
26(11):1269-75.
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