Enzastaurin (LY317615)

• CAT Number: I002225
• CAS Number: 170364-57-5
• Molecular Formula: C₃₂H₂₉N₅O₂
• Molecular Weight: 515.61
• Purity: ≥95%
• Target: PKC
• Solubility: DMSO ≥47mg/mL Water <1.2mg/mL Ethanol <1.2mg/mL
• Storage: 3 years -20C powder
• IC50: 6 nM [1]
• InChI: InChI=1S/C32H29N5O2/c1-35-19-25(23-9-2-4-11-27(23)35)29-30(32(39)34-31(29)38)26-20-37(28-12-5-3-10-24(26)28)22-13-16-36(17-14-22)18-21-8-6-7-15-33-21/h2-12,15,19-20,22H,13-14,16-18H2,1H3,(H,34,38,39)
• InChIKey: AXRCEOKUDYDWLF-UHFFFAOYSA-N
• SMILES: CN1C=C(C2=CC=CC=C21)C3=C(C(=O)NC3=O)C4=CN(C5=CC=CC=C54)C6CCN(CC6)CC7=CC=CC=N7

Enzastaurin (LY317615) is a potent PKCβ selective inhibitor with IC50 of 6 nM, 6- to 20-fold selectivity against PKCα, PKCγ and PKCε.IC50 value: 6 nM [1]Target: PKCβin vitro: investigated, including MM.1S, MM.1R, RPMI 8226 (RPMI), RPMI-Dox40 (Dox40), NCI-H929, KMS-11, OPM-2, and U266, with IC50 from 0.6-1.6 μM. Enzastaurin direct impacts human tumor cells, inducing apoptosis and suppressing proliferation in cultured tumor cells. Enzastaurin also suppresses the phosphorylation of GSK3βser9, ribosomal protein S6S240/244, and AKTThr308 while having no direct effect on VEGFR phosphorylation [1]. Enzastaurin increases apoptosis in malignant lymphocytes of CTCL. When combined with GSK3 inhibitors, enzastaurin demonstrated an enhancement of cytotoxicity levels. Treatment with a combination of enzastaurin and the GSK3 inhibitor AR-A014418 led to increased levels of β-catenin total protein and β-catenin-mediated transcription. Blocking of β-catenin-mediated transcription or small hairpin RNA (shRNA) knockdown of β-catenin induced the same cytotoxic effects as that of enzastaurin plus AR-A014418. Additionally, treatment with enzastaurin and AR-A014418 decreased the mRNA levels and surface expression of CD44 [2].in vivo: Treatment of xenografts with Enzastaurin and radiation produced greater reductions in density of microvessels than either treatment alone. The decrease in microvessel density corresponded to delayed tumor growth [3].

Reference

1:Molecular mechanism underlying the pharmacological interactions of the protein kinase C-β inhibitor enzastaurin and erlotinib in non-small cell lung cancer cells. Steen NV, Potze L, Giovannetti E, Cavazzoni A, Ruijtenbeek R, Rolfo C, Pauwels P, Peters GJ.Am J Cancer Res. 2017 Apr 1;7(4):816-830. eCollection 2017. PMID: 28469955 Free PMC Article2:Enzastaurin: A lesson in drug development. Bourhill T, Narendran A, Johnston RN.Crit Rev Oncol Hematol. 2017 Apr;112:72-79. doi: 10.1016/j.critrevonc.2017.02.003. Epub 2017 Feb 11. Review. PMID: 28325267 3:Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. Crump M, Leppä S, Fayad L, Lee JJ, Di Rocco A, Ogura M, Hagberg H, Schnell F, Rifkin R, Mackensen A, Offner F, Pinter-Brown L, Smith S, Tobinai K, Yeh SP, Hsi ED, Nguyen T, Shi P, Hahka-Kemppinen M, Thornton D, Lin B, Kahl B, Schmitz N, Savage KJ, Habermann T.J Clin Oncol. 2016 Jul 20;34(21):2484-92. doi: 10.1200/JCO.2015.65.7171. Epub 2016 May 23. PMID: 27217449 4:A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma. Li X, Fang X, Li S, Zhang W, Yang N, Cui Y, Huang H, Cai R, Lin X, Fu X, Hong H, Lin T.Oncotarget. 2016 Apr 5;7(14):18585-93. doi: 10.18632/oncotarget.7875. PMID: 26942463 Free PMC Article5:A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. Odia Y, Iwamoto FM, Moustakas A, Fraum TJ, Salgado CA, Li A, Kreisl TN, Sul J, Butman JA, Fine HA.J Neurooncol. 2016 Mar;127(1):127-35. doi: 10.1007/s11060-015-2020-x. Epub 2015 Dec 7. PMID: 26643807 6:Effects of enzastaurin and its metabolites on the QT interval in cancer patients. Welch PA, Ng WT, Darstein CL, Musib L, Lesimple T.J Clin Pharmacol. 2016 Jan;56(1):101-8. doi: 10.1002/jcph.573. Epub 2015 Aug 17. PMID: 26096682 7:The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer cell survival. Lesyk G, Fong T, Ruvolo PP, Jurasz P.J Thromb Haemost. 2015 Aug;13(8):1514-20. doi: 10.1111/jth.13010. Epub 2015 Jun 17. PMID: 25990653 8:A randomized, phase 2 study of R-CHOP plus enzastaurin vs R-CHOP in patients with intermediate- or high-risk diffuse large B-cell lymphoma. Hainsworth JD, Arrowsmith ER, McCleod M, Hsi ED, Hamid O, Shi P, Lin BK, Fayad LE.Leuk Lymphoma. 2016;57(1):216-8. doi: 10.3109/10428194.2015.1045898. Epub 2015 Oct 5. No abstract available. PMID: 25956042 9:Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status. Michaelis M, Rothweiler F, Löschmann N, Sharifi M, Ghafourian T, Cinatl J Jr.Oncotarget. 2015 Jul 10;6(19):17605-20. PMID: 25749379 Free PMC Article10:Protein kinase C β inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN). Ouaret D, Larsen AK.Cell Cycle. 2014;13(17):2697-706. doi: 10.4161/15384101.2015.945383. PMID: 25486357 Free PMC Article