enzastaurin chemical structureEnzastaurin is a synthetic bisindolyl maleimide with potential antineoplastic activity. Binding to the ATP-binding site enzastaurin selectively inhibits protein kinase C beta, an enzyme involved in the induction of vascular endothelial growth factor (VEGF)-stimulated neo-angiogenesis. Inhibition at this level halts signals promoting survival and re-growth of damaged cells. This agent may decrease tumor blood supply, preventing growth. Enzastaurin has received a great deal of attention in recent times.

Developed by Eli Lilly, enzastaurin is extensively listed in literature under the code names LY-317615 and D04014. Enzastaurin has demonstrated activity towards the PKC ß isoform with an enzastaurin IC50 of 6nM, relative to the IC50's for the α, ε and γ isoforms (39, 110 & 83 nM). Enzastaurin solubility in DMSO is limited compared to similar compounds achieving only a 7.1 mg /ml saturated solution after gentle warming. In ethanol and aqueous solutions the solubility is lower limiting buffer concentrations to 1 - 10 µM.

Figure 2: Schematic representation of mechanism of action of enzastaurin. Growth factor receptor activation initiates a phosphorylation cascade to activate key signaling proteins. Enzastaurin (ENZ), a serine/threonine kinase inhibitor, inhibits protein kinase C (PKC) activity and phosphorylation and activation of AKT, GSK3, and S6K, leading to inhibition of tumor cell proliferation, suppression of tumor induced angiogenesis, and induction of apoptosis. PLC, phospholipase C; PTEN, phosphatase and tensin homolog deleted on chromosome ten.

Figure 2: Schematic representation of mechanism of action of enzastaurin. Growth factor receptor activation initiates a phosphorylation cascade to activate key signaling proteins. Enzastaurin (ENZ), a serine/threonine kinase inhibitor, inhibits protein kinase C (PKC) activity and phosphorylation and activation of AKT, GSK3, and S6K, leading to inhibition of tumor cell proliferation, suppression of tumor induced angiogenesis, and induction of apoptosis. PLC, phospholipase C; PTEN, phosphatase and tensin homolog deleted on chromosome ten.

Enzastaurin adds specificity at low concentrations toward the PKC ß isoforms with some activity towards the α, ε and γ isoforms. In addition, it has been established that Enzastaurin has activity towards GSK3ß (also known as SER9) and towards the ribosomal protein S6 (also known as SER240/244). Against a panel of SCLC and nSCLC cell lines Enzastaurin demonstrated low µM sensitivity, inhibiting cell growth and exhibiting a decrease in GSK activity.  In various animal models enzastaurin has demonstrated prolific anti tumor activity in a range of tumor types (renal, hepatic and colon). Synergistically enzastaurin has demonstrated good sensitivity in combination with tyrosine kinase inhibitors, platinum compounds and other first line traditional treatment profiles.

Enzastaurin inhibition

Figure 3: Enzastaurin inhibits NSCLC metastasis in vivo. (AC) Number of metastasizing cells in the livers and lungs of chicken embryos treated intravenously with different concentrations of Enz (2 or 4 μ M) or DMSO, respectively. Human Alu sequences were amplified and quantified by real-time PCR.  P<0.001; P0.05. Source: British Journal of Cancer (2010) 103, 802-811. doi:10.1038/sj.bjc.6605818

Enzastaurin clinical trials are ongoing for a variety of conditions such Malignant Gliomas, refractory mantle cell lymphoma, tumors of the central nervous system, non Hodgkin's lymphomas, breast cancer and glioblastoma multiform to name only a few of the many avenues of investigation that are being pursued with this material.
Enzastaurin specifications

  • Product Number: E-2048.  Available in 1mg and 5 mg catalog sizes. Contact us for other quantities, OEM packaging or bulk inquiries.
  • CAS # 170364-57-5
  • Chemical Formula: C32H29N5O2
  • Appearance: Solid
  • Molecular Weight: 515.61
  • Purity: 99%
  • Solubility: DMSO

Sources:

  • http://www.ncbi.nlm.nih.gov
  • Br J Cancer. 2012 Feb 28;106(5):867-75. doi: 10.1038/bjc.2012.7. Epub 2012 Feb 14.
  • Department of Internal Medicine, Division of Pulmonary Medicine/Infection and Oncology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
  • http://www.selleckchem.com
  • Wikipedia
  • http://jco.ascopubs.org/content/24/25/4092.full
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  1. Enzastaurin
    Enzastaurin
    E-2048

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