Enzastaurin
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MedKoo CAT#: 201270

CAS#: 170364-57-5

Description: Enzastaurin HCL is the hydrochloride salt of enzastaurin, 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.


Price and Availability

Size
Price

10mg
USD 225
Size
Price

25mg
USD 350
Size
Price

50mg
USD 550

Enzastaurin, purity > 98%, is in stock. Current shipping out time is about 2 weeks after order is received. CoA, QC data and MSDS documents are available in one week after order is received.


Chemical Structure

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Theoretical Analysis

MedKoo Cat#: 201270
Name: Enzastaurin
CAS#: 170364-57-5
Chemical Formula: C32H29N5O2
Exact Mass: 515.23213
Molecular Weight: 515.6
Elemental Analysis: C, 74.54; H, 5.67; N, 13.58; O, 6.21


Synonym: Enzastaurin HCl; Enzastaurin Hydrochloride LY317615LY317615D04014LY 317615.

IUPAC/Chemical Name: 3-(1-methylindol-3-yl)-4-[1-[1-(pyridin-2-ylmethyl)piperidin-4-yl]indol-3-yl]pyrrole-2,5-dione hydrochloride

InChi Key: UUADYKVKJIMIPA-UHFFFAOYSA-N

InChi Code: InChI=1S/C32H29N5O2.ClH/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);1H

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.[H]Cl


Technical Data

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).

Harmonized System Code:
293490


Additional Information

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.
 
Enzastauri is a substance being studied in the treatment of certain types of cancer, including non-Hodgkin lymphoma, breast, colon, lung, ovarian, and prostate. Enzastaurin blocks certain cell signaling pathways, and may prevent the growth of new blood vessels that tumors need to grow. It is a type of serine threonine kinase inhibitor and a type of antiangiogenesis agent. Also called enzastaurin hydrochloride and LY317615.
  
  Highlight of recent results on Enzastaurin
  Highlight of recent results on Enzastaurin
Data published in 2011
Data published in 2011
P hase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma: This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related ( source: Leuk Lymphoma. 2011 Aug;52(8):1474-80. Epub 2011 Jun 8. Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. Querfeld C, Kuzel TM, Kim YH, Porcu P, Duvic M, Musiek A, Rook AH, Mark LA, Pinter-Brown L, Hamid O, Lin B, Bian Y, Boye M, Day JM, Rosen ST.)
hase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma: This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related ( source: Leuk Lymphoma. 2011 Aug;52(8):1474-80. Epub 2011 Jun 8. Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. Querfeld C, Kuzel TM, Kim YH, Porcu P, Duvic M, Musiek A, Rook AH, Mark LA, Pinter-Brown L, Hamid O, Lin B, Bian Y, Boye M, Day JM, Rosen ST.)
Data published in 2011
Data published in 2011
P hase I safety study of enzastaurin plus bortezomib:   The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional "3 + 3" design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n = 6) and anemia (n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity. Am. J. Hematol. 2011. © 2011 Wiley-Liss, Inc. ( source: Am J Hematol. 2011 Jul;86(7):573-8. doi: 10.1002/ajh.22048. Epub 2011 May 31. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R. The Multiple Myeloma/Waldenstrom's Macroglobulinemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts. irene_ghobrial@dfci.harvard.edu.).
hase I safety study of enzastaurin plus bortezomib:  
( source: Am J Hematol. 2011 Jul;86(7):573-8. doi: 10.1002/ajh.22048. Epub 2011 May 31. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R. The Multiple Myeloma/Waldenstrom's Macroglobulinemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts. irene_ghobrial@dfci.harvard.edu.).
Data published in 2010.
Data published in 2010.
Phase II, double-blind, randomized trial of capecitabine plus enzastaurin. Capecitabine is frequently used in the treatment of recurrent/progressive metastatic breast cancer (MBC) after prior anthracycline and taxane therapy. With the intention of improving the efficacy of single agent capecitabine, we initiated a randomized, double-blind, placebo-controlled Phase II study of the novel serine/threonine kinase inhibitor enzastaurin in combination with capecitabine in a heavily pretreated patient population. Patients received capecitabine 1,250 mg/m(2) twice daily plus enzastaurin 500 mg/day, or capecitabine plus placebo. The capecitabine was administered for the first 14 days of each 21 day cycle. The primary outcome was progression-free survival (PFS) using the log-rank test (1-sided significance level of 0.20). Of 109 patients assessed for eligibility, 85 were enrolled, randomized, and treated (42 and 43 patients in each respective treatment group). The study was terminated early following a preplanned futility analysis. Median PFS (95% CI) was 2.8 (2.1-4.6) months with capecitabine plus enzastaurin versus 4.3 (2.9-6.2) months with capecitabine plus placebo (adjusted hazard ratio: 1.728 [1.00-2.97]; P = 0.048). Median overall survival (95% CI) was lower with capecitabine plus enzastaurin than with capecitabine plus placebo (9.9 [7.0-16.6] months vs 14.9 [9.9-19.3] months, P = 0.181). Grade 3/4 adverse events were more frequent with capecitabine plus enzastaurin (42.9% vs 32.6%). Given the lack of PFS benefit, capecitabine plus enzastaurin is unsuitable as therapy for patients with recurrent/progressive MBC after prior anthracycline and taxane therapy. This trial is registered on www.clinicaltrials.gov (identifier: NCT00437294). ( source: Breast Cancer Res Treat. 2010 Nov;124(1):177-86. Epub 2010 Sep 3. Phase II, double-blind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy. Clemons M, Joy AA, Abdulnabi R, Kotliar M, Lynch J, Jordaan JP, Iscoe N, Gelmon K. Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Canada. mclemons@toh.on.ca).
Phase II, double-blind, randomized trial of capecitabine plus enzastaurin.
( source: Breast Cancer Res Treat. 2010 Nov;124(1):177-86. Epub 2010 Sep 3. Phase II, double-blind, randomized trial of capecitabine plus enzastaurin versus capecitabine plus placebo in patients with metastatic or recurrent breast cancer after prior anthracycline and taxane therapy. Clemons M, Joy AA, Abdulnabi R, Kotliar M, Lynch J, Jordaan JP, Iscoe N, Gelmon K. Division of Medical Oncology, The Ottawa Hospital Cancer Centre, Ottawa, Canada. mclemons@toh.on.ca).
Data published in 2010
Data published in 2010
Phase III study of enzastaurin compared with lomustine.  This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).  RESULTS:  Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001). CONCLUSION: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma. ( source: J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Department of Neurooncology, University of Heidelberg, Im Neuenheimer Feld, 400 D-69120 Heidelberg. wolfgang.wick@med.uni-heidelberg.de).
Phase III study of enzastaurin compared with lomustine.  This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).  RESULTS:  Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001). CONCLUSION: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma. ( source: J Clin Oncol. 2010 Mar 1;28(7):1168-74. Epub 2010 Feb 1. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Department of Neurooncology, University of Heidelberg, Im Neuenheimer Feld, 400 D-69120 Heidelberg. wolfgang.wick@med.uni-heidelberg.de).


References

1: Civallero M, Cosenza M, Bari A, Sacchi S. Rational combinations of enzastaurin with novel targeted agents for patients with B-cell non-Hodgkin's lymphoma. Expert Opin Investig Drugs. 2011 Aug;20(8):1029-31. Epub 2011 Jun 25. PubMed PMID: 21702717.

2: Bodo J, Sedlak J, Maciejewski JP, Almasan A, Hsi ED. HDAC inhibitors potentiate the apoptotic effect of enzastaurin in lymphoma cells. Apoptosis. 2011 Jun 11. [Epub ahead of print] PubMed PMID: 21667043.

3: Schmidinger M, Szczylik C, Sternberg CN, Kania M, Kelly CS, Decker R, Hamid O, Faelker T, Escudier B. Dose Escalation and Pharmacokinetics Study of Enzastaurin and Sunitinib Versus Placebo and Sunitinib in Patients With Metastatic Renal Cell Carcinoma. Am J Clin Oncol. 2011 Jun 4. [Epub ahead of print] PubMed PMID: 21654314.

4: Querfeld C, Kuzel TM, Kim YH, Porcu P, Duvic M, Musiek A, Rook AH, Mark LA, Pinter-Brown L, Hamid O, Lin B, Bian Y, Boye M, Day JM, Rosen ST. Multicenter phase II trial of enzastaurin in patients with relapsed or refractory advanced cutaneous T-cell lymphoma. Leuk Lymphoma. 2011 Aug;52(8):1474-80. Epub 2011 Jun 8. PubMed PMID: 21649541.

5: Ysebaert L, Morschhauser F. Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies. Expert Opin Investig Drugs. 2011 Aug;20(8):1167-74. Epub 2011 Jun 5. PubMed PMID: 21639821.

6: Ghobrial IM, Munshi NC, Harris BN, Shi P, Porter NM, Schlossman RL, Laubach JP, Anderson KC, Desaiah D, Myrand SP, Wooldridge JE, Richardson PG, Abonour R. A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma. Am J Hematol. 2011 Jul;86(7):573-8. doi: 10.1002/ajh.22048. Epub 2011 May 31. PubMed PMID: 21630305.

7: Molè D, Gagliano T, Gentilin E, Tagliati F, Pasquali C, Ambrosio MR, Pansini G, Degli Uberti EC, Zatelli MC. Targeting protein kinase C by Enzastaurin restrains proliferation and secretion in human pancreatic endocrine tumors. Endocr Relat Cancer. 2011 Jul 1;18(4):439-50. Print 2011. PubMed PMID: 21606156.

8: Rovedo MA, Krett NL, Rosen ST. Inhibition of glycogen synthase kinase-3 increases the cytotoxicity of enzastaurin. J Invest Dermatol. 2011 Jul;131(7):1442-9. doi: 10.1038/jid.2011.70. Epub 2011 Apr 7. PubMed PMID: 21471986; PubMed Central PMCID: PMC3116015.

9: Liu J, Kuo WL, Seiwert TY, Lingen M, Ciaccio MF, Jones RB, Rosner MR, Cohen EE. Effect of complementary pathway blockade on efficacy of combination enzastaurin and rapamycin. Head Neck. 2011 Mar 24. doi: 10.1002/hed.21701. [Epub ahead of print] PubMed PMID: 21438065.

10: Usha L, Sill MW, Darcy KM, Benbrook DM, Hurteau JA, Michelin DP, Mannel RS, Hanjani P, De Geest K, Godwin AK. A Gynecologic Oncology Group phase II trial of the protein kinase C-beta inhibitor, enzastaurin and evaluation of markers with potential predictive and prognostic value in persistent or recurrent epithelial ovarian and primary peritoneal malignancies. Gynecol Oncol. 2011 Jun 1;121(3):455-61. Epub 2011 Mar 17. PubMed PMID: 21414654; PubMed Central PMCID: PMC3100412.