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Trichostatin A (TSA) is a potent histone deacetylase (HDAC) inhibitor. It inhibits HDAC 1, 2, 3, 6, 10, 11 at

IC50s of less than 10 nM, with over 300-fold selectivity against class IIa HDACs.[1] TSA affects DNA

replication and gene expression by inhibiting HDAC activity and therefore altering the histone modifications

and access of DNA inside chromatin.

 

Trichostatin A induces apoptosis and cell growth arrest at both G and G/M phases. As HDACs are

overexpressed in many cancer types, TSA is widely used to probe the tumorigenesis mechanism targeting

HDAC.[2] Trichostatin A was found to prevent the differentiation of embryonic stem cell,[3] while TSA

treatment increased functional characteristics of human ESC/iPSC-derived cardiomyocytes.[4]

References

1. Lobera M, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.

   Nat Chem Biol. 2013; 9(5):319-25. Pubmed ID: 23524983

2. Timmermann S, et al. Histone acetylation and disease. Cell Mol Life Sci. 2001; 58(5-6):728-36. Review

   Pubmed ID: 11437234

3. Lee JH, et al. Histone deacetylase activity is required for embryonic stem cell differentiation. Genesis.

   2004; 38(1):32-8. Pubmed ID: 14755802

4. Otsuji TG, et al. Dynamic link between histone H3 acetylation and an increase in the functional

   characteristics of human ESC/iPSC-derived cardiomyocytes. PLoS One. 2012; 7(9):e45010 Pubmed

   ID: 11437234

AGI-5198 (IDH-C35) is a potent and selective isocitrate dehydrogenase 1 (IDH1) inhibitor specifically against

R132H/C mutants (mIDH1) with IC50 at 100 nM range. AGI-5198 does not inhibit wild-type IDH1 or any of the

examined IDH2 isoforms (IC50 > 100 µM).[1] AGI-5198 inhibits R-2-hydroxyglutarate (R-2HG) production by

mIDH1. AGI-5198 also induces demethylation of histone H3K9me3 and expression of genes associated with

gliogenic differentiation.

 

In both in vitro and in vivo studies, AGI-5198 inhibited the growth of glioma cells carrying mutated but not wild

type IDH1, yet with no appreciable changes in genome-wide DNA methylation. These data suggest that

mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

AGI-5198 could serve as a very useful chemical tool to probe the mechanism and treatment of mIDH1-

carrying tumors.

Reference

1. Rohle D, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.

   Science. 2013; 340(6132):626-30. Pubmed ID: 23558169

BI-1356 (Linagliptin) is a highly potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor (IC50 = 1 nM) for

treatment of type II diabetes. [1] BI-1356 can increase incretin levels (GLP-1 and GIP), which increases

insulin secretion and inhibits glucagon release, decreases gastric emptying, and decreases blood glucose

levels. BI-1356 shows 10,000-fold more selectivity for DPP-4 against other protease/peptidases, including

DPP-8, DPP-9, trypsin, plasmin, and thrombin.[2]

References

1. Eckhardt M, et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-

   ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally

   bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem. 2007; 50(26):6450-3. Pubmed

   ID: 18052023

2. Thomas L, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-

   ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor,

   has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors.

   J Pharmacol Exp Ther. 2008; 325(1):175-82. Pubmed ID: 18223196