Fig 1: Chemical structure of enzastaurin

Enzastaurin 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 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.

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 GSK3 (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.

 

 

 

 

 

 

 

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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