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Details

Stereochemistry ACHIRAL
Molecular Formula C32H29N5O2.ClH.H2O
Molecular Weight 570.081
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of ENZASTAURIN HYDROCHLORIDE MONOHYDRATE

SMILES

O.Cl.CN1C=C(C2=C1C=CC=C2)C3=C(C(=O)NC3=O)C4=CN(C5CCN(CC6=CC=CC=N6)CC5)C7=CC=CC=C47

InChI

InChIKey=NCSOZDYVYDZHMT-UHFFFAOYSA-N
InChI=1S/C32H29N5O2.ClH.H2O/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;1H2

HIDE SMILES / InChI

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula H2O
Molecular Weight 18.0153
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Molecular Formula C32H29N5O2
Molecular Weight 515.605
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Enzastaurin is a serine/threonine kinase inhibitor that showed antiangiogenic, antiproliferative, and proapoptotic properties in vitro and antitumor activity in vivo in a xenograft Waldenström macroglobulinemia (WM) model. Enzastaurin (LY317615) is a potent PKCβ selective inhibitor. Enzastaurin suppresses angiogenesis and was advanced for clinical development based upon this antiangiogenic activity. Enzastaurin suppresses tumor growth through multiple mechanisms: direct suppression of tumor cell proliferation and the induction of tumor cell death coupled to the indirect effect of suppressing tumor-induced angiogenesis. Enzastaurin is an orally administered drug that was intended for the treatment of solid and haematological cancers. Enzastaurin had shown encouraging preclinical results for the prevention of angiogenesis, inhibition of proliferation and induction of apoptosis as well as showing limited cytotoxicity within phase I clinical trials. However, during its assessment in phase II and III clinical trials the efficacy of enzastaurin was poor both in combination with other drugs and as a single agent. Eli Lilly discontinued development of enzastaurin after top-line data from the double-blind, international Phase III PRELUDE trial in 758 DLBCL patients showed that enzastaurin missed the primary endpoint of improving DFS vs. placebo.

Originator

Curator's Comment: # Eli Lilly

Approval Year

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Enzastaurin and pemetrexed exert synergistic antitumor activity in thyroid cancer cell lines in vitro.
2005 Dec
Enzastaurin, a protein kinase Cbeta- selective inhibitor, and its potential application as an anticancer agent in lung cancer.
2007 Aug 1
Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.
2007 May 1
The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines.
2008 Jul
Sequence-dependent, synergistic antiproliferative and proapoptotic effects of the combination of cytotoxic drugs and enzastaurin, a protein kinase Cbeta inhibitor, in non-small cell lung cancer cells.
2008 Jun
Enzastaurin.
2008 Jun
Enzastaurin renders MCF-7 breast cancer cells sensitive to radiation through reversal of radiation-induced activation of protein kinase C.
2008 Jun
Enzastaurin, an oral serine/threonine kinase inhibitor, as second- or third-line therapy of non-small-cell lung cancer.
2008 Mar 1
Enzastaurin, a protein kinase C beta inhibitor, suppresses signaling through the ribosomal S6 kinase and bad pathways and induces apoptosis in human gastric cancer cells.
2008 Mar 15
Protein kinase C beta in malignant pleural mesothelioma.
2008 Oct
Waldenstrom macroglobulinemia.
2008 Oct 18
Molecular pathways involved in the synergistic interaction of the PKC beta inhibitor enzastaurin with the antifolate pemetrexed in non-small cell lung cancer cells.
2008 Sep 2
In Vivo Measurements of Tumor Metabolism and Growth after Administration of Enzastaurin Using Small Animal FDG Positron Emission Tomography.
2009
Design of Phase II cancer trials for evaluation of cytostatic/cytotoxic agents.
2009
Synergistic anti-tumor efficacy of lovastatin and protein kinase C-beta inhibitor in hepatocellular carcinoma.
2009 Aug
Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.
2009 Feb 12
Protein kinase Cbeta is an effective target for chemoprevention of colon cancer.
2009 Feb 15
Synergistic effect of Sorafenib and Sunitinib with Enzastaurin, a selective protein kinase C inhibitor in renal cell carcinoma cell lines.
2009 May 18
Conformationally constrained analogues of diacylglycerol (DAG). 31. Modulation of the biological properties of diacylgycerol lactones (DAG-lactones) containing rigid-rod acyl groups separated from the core lactone by spacer units of different lengths.
2009 May 28
Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second-line therapy in patients with advanced non-small cell lung cancer.
2010 Mar
Long-term follow-up of chemonaive patients with asymptomatic metastatic colorectal cancer treated with enzastaurin in a window of opportunity phase II study.
2010 May
Patents

Sample Use Guides

1125 mg loading dose then 500 mg, oral, daily, until disease progression or maximum of 3 years
Route of Administration: Oral
In the BON1 cell line Enzastaurin inhibited cell proliferation at 5 and 10 uM by inducing caspase-mediated apoptosis, and reduced phosphorylation of glycogen synthetase kinase 3β (GSK3β) and of Akt, both downstream targets of PKC pathway and pharmacodynamic markers for Enzastaurin.
Substance Class Chemical
Created
by admin
on Sat Dec 16 10:09:42 UTC 2023
Edited
by admin
on Sat Dec 16 10:09:42 UTC 2023
Record UNII
7P5KLU0N3Q
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ENZASTAURIN HYDROCHLORIDE MONOHYDRATE
Common Name English
1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-, HYDROCHLORIDE, HYDRATE (1:1:1)
Systematic Name English
1H-PYRROLE-2,5-DIONE, 3-(1-METHYL-1H-INDOL-3-YL)-4-(1-(1-(2-PYRIDINYLMETHYL)-4-PIPERIDINYL)-1H-INDOL-3-YL)-, MONOHYDROCHLORIDE, MONOHYDRATE
Brand Name English
Code System Code Type Description
FDA UNII
7P5KLU0N3Q
Created by admin on Sat Dec 16 10:09:42 UTC 2023 , Edited by admin on Sat Dec 16 10:09:42 UTC 2023
PRIMARY
CAS
647031-15-0
Created by admin on Sat Dec 16 10:09:42 UTC 2023 , Edited by admin on Sat Dec 16 10:09:42 UTC 2023
PRIMARY
PUBCHEM
86278309
Created by admin on Sat Dec 16 10:09:42 UTC 2023 , Edited by admin on Sat Dec 16 10:09:42 UTC 2023
PRIMARY
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