WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H201270
CAS#: 170364-57-5 (free base)
Description: Enzastaurin, also known as DB-102 and LY317615, is a synthetic macrocyclic bisindolemaleimide 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. This agent may decrease tumor blood supply and so tumor burden.
Hodoodo Cat#: H201270
Name: Enzastaurin free base
CAS#: 170364-57-5 (free base)
Chemical Formula: C32H29N5O2
Exact Mass: 515.23
Molecular Weight: 515.600
Elemental Analysis: C, 74.54; H, 5.67; N, 13.58; O, 6.21
Related CAS #: 170364-57-5 (free base); 359017-79-1 (HCl) 365253-37-8 (2HCl),
Synonym: LY317615; LY-317615; LY317615; D04014; D-04014; D 04014; DB-102; DB102; DB102; Enzastaurin; Enzastaurin free base;
IUPAC/Chemical Name: 3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione
InChi Key: AXRCEOKUDYDWLF-UHFFFAOYSA-N
InChi Code: 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)
SMILES Code: O=C(C(C1=CN(C)C2=C1C=CC=C2)=C3C4=CN(C5CCN(CC6=NC=CC=C6)CC5)C7=C4C=CC=C7)NC3=O
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 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
More Info: Enzastaurin is a synthetic bisindolemaleimide 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. This agent may decrease tumor blood supply, preventing growth.
| Biological target: | Enzastaurin (LY317615) is a PKCβ inhibitor with an IC50 of 6 nM, showing 6- to 20-fold selectivity over PKCα, PKCγ and PKCε. |
| In vitro activity: | Enzastaurin (10(-8) -10(-6) m) potentiated aggregation of prostacyclin-washed platelets and caused an increase in VEGF release from α-granules that, in turn, promoted cancer cell survival. In platelet-rich plasma, 10(-6) m enzastaurin inhibited platelet aggregation, but not 10(-7) m enzastaurin, which also failed to suppress VEGF secretion. Reference: J Thromb Haemost. 2015 Aug;13(8):1514-20. https://pubmed.ncbi.nlm.nih.gov/25990653/ |
| In vivo activity: | A two-way ANOVA demonstrated a significant interaction [F (24,168) = 2.19, p = 0.002] and significant main effects of time [F (12, 168) = 61.86, p < 0.0001] and enzastaurin dose [F (2,14) = 8.36, p = 0.004] (Fig. 1a). In data converted to AUC, a one-way ANOVA revealed rats treated with 1 nmol enzastaurin had significantly lower levels of locomotor activity compared with vehicle treated rats [F (2,14) = 6.02, p = 0.01] (Fig. 1b). Reference: Psychopharmacology (Berl). 2019 Nov; 236(11): 3231–3242. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832797/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMF | 16.6 | 32.20 | |
| DMF:PBS (pH 7.2) (1:3) | 0.3 | 0.48 |
The following data is based on the product molecular weight 515.60 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 |
| Formulation protocol: | 1. Lesyk G, Fong T, Ruvolo PP, Jurasz P. The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer cell survival. J Thromb Haemost. 2015 Aug;13(8):1514-20. doi: 10.1111/jth.13010. Epub 2015 Jun 17. PMID: 25990653. 2. Michaelis M, Rothweiler F, Löschmann N, Sharifi M, Ghafourian T, Cinatl J Jr. Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status. Oncotarget. 2015 Jul 10;6(19):17605-20. doi: 10.18632/oncotarget.2889. PMID: 25749379; PMCID: PMC4627332. 3. Altshuler RD, Carpenter CA, Franke TJ, Gnegy ME, Jutkiewicz EM. The protein kinase Cβ-selective inhibitor, enzastaurin, attenuates amphetamine-stimulated locomotor activity and self-administration behaviors in rats. Psychopharmacology (Berl). 2019 Nov;236(11):3231-3242. doi: 10.1007/s00213-019-05278-0. Epub 2019 May 27. Erratum in: Psychopharmacology (Berl). 2019 Jul 3;: PMID: 31134292; PMCID: PMC6832797. 4. Willeman MN, Mennenga SE, Siniard AL, Corneveaux JJ, De Both M, Hewitt LT, Tsang CWS, Caselli J, Braden BB, Bimonte-Nelson HA, Huentelman MJ. The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats. PLoS One. 2018 Jun 5;13(6):e0198256. doi: 10.1371/journal.pone.0198256. PMID: 29870545; PMCID: PMC5988320. |
| In vitro protocol: | 1. Lesyk G, Fong T, Ruvolo PP, Jurasz P. The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer cell survival. J Thromb Haemost. 2015 Aug;13(8):1514-20. doi: 10.1111/jth.13010. Epub 2015 Jun 17. PMID: 25990653. 2. Michaelis M, Rothweiler F, Löschmann N, Sharifi M, Ghafourian T, Cinatl J Jr. Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status. Oncotarget. 2015 Jul 10;6(19):17605-20. doi: 10.18632/oncotarget.2889. PMID: 25749379; PMCID: PMC4627332. |
| In vivo protocol: | 1. Altshuler RD, Carpenter CA, Franke TJ, Gnegy ME, Jutkiewicz EM. The protein kinase Cβ-selective inhibitor, enzastaurin, attenuates amphetamine-stimulated locomotor activity and self-administration behaviors in rats. Psychopharmacology (Berl). 2019 Nov;236(11):3231-3242. doi: 10.1007/s00213-019-05278-0. Epub 2019 May 27. Erratum in: Psychopharmacology (Berl). 2019 Jul 3;: PMID: 31134292; PMCID: PMC6832797. 2. Willeman MN, Mennenga SE, Siniard AL, Corneveaux JJ, De Both M, Hewitt LT, Tsang CWS, Caselli J, Braden BB, Bimonte-Nelson HA, Huentelman MJ. The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats. PLoS One. 2018 Jun 5;13(6):e0198256. doi: 10.1371/journal.pone.0198256. PMID: 29870545; PMCID: PMC5988320. |
1: Li ZY, Liang C, Ding M, Weng XQ, Sheng Y, Wu J, Lu H, Cai X. Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells. Am J Transl Res. 2020 Dec 15;12(12):7836-7854. PMID: 33437364; PMCID: PMC7791522.
2: Nowakowski GS, Zhu J, Zhang Q, Brody J, Sun X, Maly J, Song Y, Rizvi S, Song Y, Lansigan F, Jing H, Cao J, Lue JK, Luo W, Zhang L, Li L, Han I, Sun J, Jivani M, Liu Y, Heineman T, Smith SD. ENGINE: a Phase III randomized placebo controlled study of enzastaurin/R-CHOP as frontline therapy in high-risk diffuse large B-cell lymphoma patients with the genomic biomarker DGM1. Future Oncol. 2020 May;16(15):991-999. doi: 10.2217/fon-2020-0176. Epub 2020 Apr 6. PMID: 32250167.
3: Ma G, Gezer D, Herrmann O, Feldberg K, Schemionek M, Jawhar M, Reiter A, Brümmendorf TH, Koschmieder S, Chatain N. LCP1 triggers mTORC2/AKT activity and is pharmacologically targeted by enzastaurin in hypereosinophilia. Mol Carcinog. 2020 Jan;59(1):87-103. doi: 10.1002/mc.23131. Epub 2019 Nov 6. PMID: 31691359.
4: Altshuler RD, Carpenter CA, Franke TJ, Gnegy ME, Jutkiewicz EM. Correction to: The protein kinase Cβ-selective inhibitor, enzastaurin, attenuates amphetamine-stimulated locomotor activity and self-administration behaviors in rats. Psychopharmacology (Berl). 2019 Nov;236(11):3243. doi: 10.1007/s00213-019-05312-1. Erratum for: Psychopharmacology (Berl). 2019 Nov;236(11):3231-3242. PMID: 31270556.
5: Liang C, Ding M, Weng XQ, Sheng Y, Wu J, Li ZY, Cai X. Combination of enzastaurin and ATRA exerts dose-dependent dual effects on ATRA-resistant acute promyelocytic leukemia cells. Am J Cancer Res. 2019 May 1;9(5):906-926. PMID: 31218101; PMCID: PMC6556610.
6: Altshuler RD, Carpenter CA, Franke TJ, Gnegy ME, Jutkiewicz EM. The protein kinase Cβ-selective inhibitor, enzastaurin, attenuates amphetamine-stimulated locomotor activity and self-administration behaviors in rats. Psychopharmacology (Berl). 2019 Nov;236(11):3231-3242. doi: 10.1007/s00213-019-05278-0. Epub 2019 May 27. Erratum in: Psychopharmacology (Berl). 2019 Jul 3;: PMID: 31134292; PMCID: PMC6832797.
7: He Y, Li J, Ding N, Wang X, Deng L, Xie Y, Ying Z, Liu W, Ping L, Zhang C, Song Y, Zhu J. Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma. J Exp Clin Cancer Res. 2019 Feb 18;38(1):86. doi: 10.1186/s13046-019-1076-4. PMID: 30777096; PMCID: PMC6379963.
8: Willeman MN, Mennenga SE, Siniard AL, Corneveaux JJ, De Both M, Hewitt LT, Tsang CWS, Caselli J, Braden BB, Bimonte-Nelson HA, Huentelman MJ. The PKC-β selective inhibitor, Enzastaurin, impairs memory in middle-aged rats. PLoS One. 2018 Jun 5;13(6):e0198256. doi: 10.1371/journal.pone.0198256. PMID: 29870545; PMCID: PMC5988320.
9: Steen NV, Potze L, Giovannetti E, Cavazzoni A, Ruijtenbeek R, Rolfo C, Pauwels P, Peters GJ. Molecular mechanism underlying the pharmacological interactions of the protein kinase C-β inhibitor enzastaurin and erlotinib in non-small cell lung cancer cells. Am J Cancer Res. 2017 Apr 1;7(4):816-830. PMID: 28469955; PMCID: PMC5411790.
10: Bourhill T, Narendran A, Johnston RN. Enzastaurin: A lesson in drug development. Crit Rev Oncol Hematol. 2017 Apr;112:72-79. doi: 10.1016/j.critrevonc.2017.02.003. Epub 2017 Feb 11. PMID: 28325267.
11: 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. 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. J Clin Oncol. 2016 Jul 20;34(21):2484-92. doi: 10.1200/JCO.2015.65.7171. Epub 2016 May 23. PMID: 27217449.
12: Li X, Fang X, Li S, Zhang W, Yang N, Cui Y, Huang H, Cai R, Lin X, Fu X, Hong H, Lin T. A pharmacokinetic and safety study of a fixed oral dose of enzastaurin HCl in native Chinese patients with refractory solid tumors and lymphoma. Oncotarget. 2016 Apr 5;7(14):18585-93. doi: 10.18632/oncotarget.7875. PMID: 26942463; PMCID: PMC4951311.
13: Odia Y, Iwamoto FM, Moustakas A, Fraum TJ, Salgado CA, Li A, Kreisl TN, Sul J, Butman JA, Fine HA. A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. J Neurooncol. 2016 Mar;127(1):127-35. doi: 10.1007/s11060-015-2020-x. Epub 2015 Dec 7. PMID: 26643807.
14: Welch PA, Ng WT, Darstein CL, Musib L, Lesimple T. Effects of enzastaurin and its metabolites on the QT interval in cancer patients. J Clin Pharmacol. 2016 Jan;56(1):101-8. doi: 10.1002/jcph.573. Epub 2015 Aug 17. PMID: 26096682.
15: Lesyk G, Fong T, Ruvolo PP, Jurasz P. The potential of enzastaurin to enhance platelet aggregation and growth factor secretion: implications for cancer cell survival. J Thromb Haemost. 2015 Aug;13(8):1514-20. doi: 10.1111/jth.13010. Epub 2015 Jun 17. PMID: 25990653.
16: Hainsworth JD, Arrowsmith ER, McCleod M, Hsi ED, Hamid O, Shi P, Lin BK, Fayad LE. 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. Leuk Lymphoma. 2016;57(1):216-8. doi: 10.3109/10428194.2015.1045898. Epub 2015 Oct 5. PMID: 25956042.
17: Michaelis M, Rothweiler F, Löschmann N, Sharifi M, Ghafourian T, Cinatl J Jr. Enzastaurin inhibits ABCB1-mediated drug efflux independently of effects on protein kinase C signalling and the cellular p53 status. Oncotarget. 2015 Jul 10;6(19):17605-20. doi: 10.18632/oncotarget.2889. PMID: 25749379; PMCID: PMC4627332.
18: Ouaret D, Larsen AK. Protein kinase C β inhibition by enzastaurin leads to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability (CIN). Cell Cycle. 2014;13(17):2697-706. doi: 10.4161/15384101.2015.945383. PMID: 25486357; PMCID: PMC4614369.
19: Kilburn LB, Kocak M, Decker RL, Wetmore C, Chintagumpala M, Su J, Goldman S, Banerjee A, Gilbertson R, Fouladi M, Kun L, Boyett JM, Blaney SM. A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study. Neuro Oncol. 2015 Feb;17(2):303-11. doi: 10.1093/neuonc/nou114. Epub 2014 Nov 27. PMID: 25431212; PMCID: PMC4288513.
20: Cosenza M, Civallero M, Pozzi S, Marcheselli L, Bari A, Sacchi S. The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines. Hematol Oncol. 2015 Dec;33(4):166-75. doi: 10.1002/hon.2179. Epub 2014 Nov 13. Erratum in: Hematol Oncol. 2016 Jun;34(2):117. PMID: 25394177.
