WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205795
Description: ZSTK474 is a novel orally applicable phosphoinositide 3-kinase-specific inhibitor that strongly inhibits cancer cell proliferation. Combination treatment using X-rays then ZSTK474 given orally for 8 days, starting 24h post-irradiation, significantly enhanced cell growth inhibition. The combined effect was also observed for clonogenic survival with continuous ZSTK474 treatment. Western blot analysis showed enhanced phosphorylation of Akt and GSK-3β by X-irradiation, whereas phosphorylation was inhibited by ZSTK474 treatment alone. Treatment with ZSTK474 after X-irradiation also inhibited phosphorylation, and remarkably inhibited xenograft tumor growth.
MedKoo Cat#: 205795
Chemical Formula: C19H21F2N7O2
Exact Mass: 417.17248
Molecular Weight: 417.41255
Elemental Analysis: C, 54.67; H, 5.07; F, 9.10; N, 23.49; O, 7.67
Synonym: ZSTK474; ZSTK-474; ZSTK 474;.
IUPAC/Chemical Name: 4,4'-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazine-2,4-diyl)dimorpholine
InChi Key: HGVNLRPZOWWDKD-UHFFFAOYSA-N
InChi Code: InChI=1S/C19H21F2N7O2/c20-15(21)16-22-13-3-1-2-4-14(13)28(16)19-24-17(26-5-9-29-10-6-26)23-18(25-19)27-7-11-30-12-8-27/h1-4,15H,5-12H2
SMILES Code: FC(C1=NC2=CC=CC=C2N1C3=NC(N4CCOCC4)=NC(N5CCOCC5)=N3)F
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: soluble in DMSO, not soluble in water.
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
The following data is based on the product molecular weight 417.41255 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
1: Tamura N. Recent findings on phosphoinositide-3 kinase in rheumatic diseases. Nihon Rinsho Meneki Gakkai Kaishi. 2012;35(1):8-13. PubMed PMID: 22374437.
2: Haruta K, Mori S, Tamura N, Sasaki A, Nagamine M, Yaguchi SI, Kamachi F, Enami J, Kobayashi S, Yamori T, Takasaki Y. Inhibitory effects of ZSTK474, a phosphatidylinositol 3-kinase inhibitor, on adjuvant-induced arthritis in rats. Inflamm Res. 2012 Feb 15. [Epub ahead of print] PubMed PMID: 22349137.
3: Kong D, Yamori T. JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs. Bioorg Med Chem. 2012 Mar 15;20(6):1947-51. Epub 2012 Jan 21. PubMed PMID: 22336246.
4: Smith GC, Ong WK, Rewcastle GW, Kendall JD, Han W, Shepherd PR. Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo. Biochem J. 2012 Feb 15;442(1):161-9. PubMed PMID: 22142257.
5: Dan S, Okamura M, Mukai Y, Yoshimi H, Inoue Y, Hanyu A, Sakaue-Sawano A, Imamura T, Miyawaki A, Yamori T. ZSTK474, a specific phosphatidylinositol 3-kinase inhibitor, induces G1 arrest of the cell cycle in vivo. Eur J Cancer. 2011 Nov 14. [Epub ahead of print] PubMed PMID: 22088482.
6: Yang S, Xiao X, Meng X, Leslie KK. A mechanism for synergy with combined mTOR and PI3 kinase inhibitors. PLoS One. 2011;6(10):e26343. Epub 2011 Oct 19. PubMed PMID: 22039466; PubMed Central PMCID: PMC3198385.
7: Duong HQ, Kim HJ, Kang HJ, Seong YS, Bae I. ZSTK474, a PI3K inhibitor, suppresses proliferation and sensitizes human pancreatic adenocarcinoma cells to gemcitabine. Oncol Rep. 2012 Jan;27(1):182-8. doi: 10.3892/or.2011.1503. Epub 2011 Oct 12. PubMed PMID: 21993922.
8: Rewcastle GW, Gamage SA, Flanagan JU, Frederick R, Denny WA, Baguley BC, Kestell P, Singh R, Kendall JD, Marshall ES, Lill CL, Lee WJ, Kolekar S, Buchanan CM, Jamieson SM, Shepherd PR. Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). J Med Chem. 2011 Oct 27;54(20):7105-26. Epub 2011 Sep 27. PubMed PMID: 21882832.
9: Anzai K, Sekine-Suzuki E, Ueno M, Okamura M, Yoshimi H, Dan S, Yaguchi S, Enami J, Yamori T, Okayasu R. Effectiveness of combined treatment using X-rays and a phosphoinositide 3-kinase inhibitor, ZSTK474, on proliferation of HeLa cells in vitro and in vivo. Cancer Sci. 2011 Jun;102(6):1176-80. doi: 10.1111/j.1349-7006.2011.01916.x. Epub 2011 Apr 4. PubMed PMID: 21352422.
10: Kong D, Yamazaki K, Yamori T. Discovery of phosphatidylinositol 3-kinase inhibitory compounds from the Screening Committee of Anticancer Drugs (SCADS) library. Biol Pharm Bull. 2010;33(9):1600-4. PubMed PMID: 20823581.
Z STK474 directly inhibited PI3K activity more efficiently than the PI3K inhibitor LY294002. At concentrations of 1 microM, ZSTK474 and LY2194002 reduced PI3K activity to 4.7% (95% confidence interval [CI] = 3.2% to 6.1%) and 44.6% (95% CI = 38.9% to 50.3%), respectively, of the untreated control level. Molecular modeling of the PI3K-ZSTK474 complex indicated that ZSTK474 could bind to the ATP-binding pocket of PI3K. ZSTK474 inhibited phosphorylation of signaling components downstream from PI3K, such as Akt and glycogen synthase kinase 3beta, and mediated a decrease in cyclin D1 levels. ZSTK474 administered orally to mice had strong antitumor activity against human cancer xenografts without toxic effects in critical organs. Akt phosphorylation was reduced in xenograft tumors after oral administration of ZSTK474. CONCLUSION: ZSTK474 is a new PI3K inhibitor with strong antitumor activity against human cancer xenografts without toxic effects in critical organs. ZSTK474 merits further investigation as an anticancer drug. (source: J Natl Cancer Inst. 2006 Apr 19;98(8):545-56.)