ENMD-2076
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MedKoo CAT#: 201264

CAS#: 934353-76-1 (free base)

Description: ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers.


Chemical Structure

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ENMD-2076
CAS# 934353-76-1 (free base)

Theoretical Analysis

MedKoo Cat#: 201264
Name: ENMD-2076
CAS#: 934353-76-1 (free base)
Chemical Formula: C21H25N7
Exact Mass: 375.21714
Molecular Weight: 375.47
Elemental Analysis: C, 67.18; H, 6.71; N, 26.11

Price and Availability

Size Price Availability Quantity
50.0mg USD 450.0 2 weeks
100.0mg USD 650.0 2 weeks
200.0mg USD 950.0 2 weeks
500.0mg USD 1750.0 2 weeks
1.0g USD 2650.0 2 weeks
2.0g USD 4650.0 2 weeks
5.0g USD 6950.0 2 weeks
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Related CAS #: 1291074-87-7 (tartrate)   934353-76-1 (free base)   1453868-32-0 (tartrate)    

Synonym: ENMD2076; ENMD 2076; ENMD-2076.

IUPAC/Chemical Name: (E)-N-(5-methyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-styrylpyrimidin-4-amine.

InChi Key: BLQYVHBZHAISJM-CMDGGOBGSA-N

InChi Code: InChI=1S/C21H25N7/c1-16-14-20(26-25-16)23-19-15-21(28-12-10-27(2)11-13-28)24-18(22-19)9-8-17-6-4-3-5-7-17/h3-9,14-15H,10-13H2,1-2H3,(H2,22,23,24,25,26)/b9-8+

SMILES Code: CN1CCN(C2=CC(NC3=NNC(C)=C3)=NC(/C=C/C4=CC=CC=C4)=N2)CC1

Appearance: white 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: >2 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

Product Data:

Biological target: ENMD-2076 is a multi-targeted kinase inhibitor with IC50s of 1.86, 14, 58.2, 15.9, 92.7, 70.8, 56.4 nM for Aurora A, Flt3, KDR/VEGFR2, Flt4/VEGFR3, FGFR1, FGFR2, Src, PDGFRα, respectively.
In vitro activity: Fig. 1A depicts the in vitro response of ENMD-2076 treatment in breast cancer cell lines where IC50 values ranged from 0.25 to 16.1 μmol/L. This study defined ENMD-2076-sensitive and -resistant cell lines as IC50 < 1 μmol/L and IC50 > 3 μmol/L, respectively. Using this sensitivity cut-off, 8 and 11 cell lines from the breast cancer panel were classified as sensitive and resistant to ENMD-2076, respectively. Interestingly, the cell lines that were most sensitive to ENMD-2076 were enriched for TNBC, while the more resistant lines were enriched for HER2 and luminal subtypes (Fisher's exact test, p = 0.0045) (Fig. 1B). Reference: Clin Cancer Res. 2013 Jan 1; 19(1): 291–303. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537923/
In vivo activity: As depicted in Figure 1A, ENMD-2076 treatment resulted in statistically significant tumor growth inhibition in PDX models CU_TNBC_002 and CU_TNBC_005 at day 30 (p < 0.0001, TGI: 71.3%; and p < 0.001, TGI: 66.1%, respectively). The PDX model CU_TNBC_004 was intrinsically resistant to treatment with ENMD-2076 (TGI: 37.0%). Reference: Front Oncol. 2017; 7: 94. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430301/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO:PBS (pH 7.2) (1:1) 0.5 1.33
DMF 20.0 53.27
Ethanol 3.0 7.99
Water 1.0 2.66

Preparing Stock Solutions

The following data is based on the product molecular weight 375.47 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.

Recalculate based on batch purity %
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. Zhong S, Bai Y, Wu B, Ge J, Jiang S, Li W, Wang X, Ren J, Xu H, Chen Y, Zhao G. Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats. Aging (Albany NY). 2019 Nov 9;11(21):9738-9766. doi: 10.18632/aging.102422. Epub 2019 Nov 9. PMID: 31706255; PMCID: PMC6874459. 2. Diamond JR, Eckhardt SG, Tan AC, Newton TP, Selby HM, Brunkow KL, Kachaeva MI, Varella-Garcia M, Pitts TM, Bray MR, Fletcher GC, Tentler JJ. Predictive biomarkers of sensitivity to the aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models. Clin Cancer Res. 2013 Jan 1;19(1):291-303. doi: 10.1158/1078-0432.CCR-12-1611. Epub 2012 Nov 7. PMID: 23136197; PMCID: PMC3537923. 3. Ionkina AA, Tentler JJ, Kim J, Capasso A, Pitts TM, Ryall KA, Howison RR, Kabos P, Sartorius CA, Tan AC, Eckhardt SG, Diamond JR. Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer. Front Oncol. 2017 May 15;7:94. doi: 10.3389/fonc.2017.00094. PMID: 28555173; PMCID: PMC5430301. 4. Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, Sidor CF, Bray MR. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011 Jan;10(1):126-37. doi: 10.1158/1535-7163.MCT-10-0574. Epub 2010 Dec 21. PMID: 21177375.
In vitro protocol: 1. Zhong S, Bai Y, Wu B, Ge J, Jiang S, Li W, Wang X, Ren J, Xu H, Chen Y, Zhao G. Selected by gene co-expression network and molecular docking analyses, ENMD-2076 is highly effective in glioblastoma-bearing rats. Aging (Albany NY). 2019 Nov 9;11(21):9738-9766. doi: 10.18632/aging.102422. Epub 2019 Nov 9. PMID: 31706255; PMCID: PMC6874459. 2. Diamond JR, Eckhardt SG, Tan AC, Newton TP, Selby HM, Brunkow KL, Kachaeva MI, Varella-Garcia M, Pitts TM, Bray MR, Fletcher GC, Tentler JJ. Predictive biomarkers of sensitivity to the aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models. Clin Cancer Res. 2013 Jan 1;19(1):291-303. doi: 10.1158/1078-0432.CCR-12-1611. Epub 2012 Nov 7. PMID: 23136197; PMCID: PMC3537923.
In vivo protocol: 1. Ionkina AA, Tentler JJ, Kim J, Capasso A, Pitts TM, Ryall KA, Howison RR, Kabos P, Sartorius CA, Tan AC, Eckhardt SG, Diamond JR. Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer. Front Oncol. 2017 May 15;7:94. doi: 10.3389/fonc.2017.00094. PMID: 28555173; PMCID: PMC5430301. 2. Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, Sidor CF, Bray MR. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011 Jan;10(1):126-37. doi: 10.1158/1535-7163.MCT-10-0574. Epub 2010 Dec 21. PMID: 21177375.

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1: Shiomitsu K, Sajo E, Rubin C, Sehgal I. The radiosensitizing effect of the aurora kinase inhibitors, ENMD-2076, on canine mast cell tumours in vitro. Vet Comp Oncol. 2013 Jun 13. doi: 10.1111/vco.12046. [Epub ahead of print] PubMed PMID: 23763774; PubMed Central PMCID: PMC3812382.

2: Diamond JR, Eckhardt SG, Tan AC, Newton TP, Selby HM, Brunkow KL, Kachaeva MI, Varella-Garcia M, Pitts TM, Bray MR, Fletcher GC, Tentler JJ. Predictive biomarkers of sensitivity to the aurora and angiogenic kinase inhibitor ENMD-2076 in preclinical breast cancer models. Clin Cancer Res. 2013 Jan 1;19(1):291-303. doi: 10.1158/1078-0432.CCR-12-1611. Epub 2012 Nov 7. PubMed PMID: 23136197; PubMed Central PMCID: PMC3537923.

3: Cao H, Li M, Qian WB. [Killing effect of aurora kinase inhibitor ENMD-2076 on acute myelogenous leukemia cells]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2012 Sep;41(5):479-84. Chinese. PubMed PMID: 23086638.

4: Matulonis UA, Lee J, Lasonde B, Tew WP, Yehwalashet A, Matei D, Behbakht K, Grothusen J, Fleming G, Lee NK, Arnott J, Bray MR, Fletcher G, Brokx RD, Castonguay V, Mackay H, Sidor CF, Oza AM. ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer. 2013 Jan;49(1):121-31. doi: 10.1016/j.ejca.2012.07.020. Epub 2012 Aug 21. PubMed PMID: 22921155.

5: How J, Yee K. ENMD-2076 for hematological malignancies. Expert Opin Investig Drugs. 2012 May;21(5):717-32. doi: 10.1517/13543784.2012.668882. Epub 2012 Mar 8. Review. PubMed PMID: 22397360.

6: Zhang S, Farag SS. From cell biology to therapy: ENMD-2076 in the treatment of multiple myeloma. Expert Opin Investig Drugs. 2011 Jul;20(7):1015-28. doi: 10.1517/13543784.2011.584869. Epub 2011 May 26. Review. PubMed PMID: 21615212.

7: Fletcher GC, Brokx RD, Denny TA, Hembrough TA, Plum SM, Fogler WE, Sidor CF, Bray MR. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action. Mol Cancer Ther. 2011 Jan;10(1):126-37. doi: 10.1158/1535-7163.MCT-10-0574. Epub 2010 Dec 21. PubMed PMID: 21177375.

8: Diamond JR, Bastos BR, Hansen RJ, Gustafson DL, Eckhardt SG, Kwak EL, Pandya SS, Fletcher GC, Pitts TM, Kulikowski GN, Morrow M, Arnott J, Bray MR, Sidor C, Messersmith W, Shapiro GI. Phase I safety, pharmacokinetic, and pharmacodynamic study of ENMD-2076, a novel angiogenic and Aurora kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2011 Feb 15;17(4):849-60. doi: 10.1158/1078-0432.CCR-10-2144. Epub 2010 Dec 3. PubMed PMID: 21131552; PubMed Central PMCID: PMC3867298.

9: Wang X, Sinn AL, Pollok K, Sandusky G, Zhang S, Chen L, Liang J, Crean CD, Suvannasankha A, Abonour R, Sidor C, Bray MR, Farag SS. Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma. Br J Haematol. 2010 Aug;150(3):313-25. doi: 10.1111/j.1365-2141.2010.08248.x. Epub 2010 Jun 15. PubMed PMID: 20560971.

10: Tentler JJ, Bradshaw-Pierce EL, Serkova NJ, Hasebroock KM, Pitts TM, Diamond JR, Fletcher GC, Bray MR, Eckhardt SG. Assessment of the in vivo antitumor effects of ENMD-2076, a novel multitargeted kinase inhibitor, against primary and cell line-derived human colorectal cancer xenograft models. Clin Cancer Res. 2010 Jun 1;16(11):2989-98. doi: 10.1158/1078-0432.CCR-10-0325. Epub 2010 Apr 20. PubMed PMID: 20406842; PubMed Central PMCID: PMC3928713.



Additional Information

ENMD-2076 is a novel orally-active, Aurora A/angiogenic kinase inhibitor with potent activity against Aurora A and multiple tyrosine kinases linked to cancer and inflammatory diseases. ENMD-2076 is relatively selective for the Aurora A isoform in comparison to Aurora B. Aurora kinases are key regulators of the process of mitosis, or cell division, and are often over-expressed in human cancers. ENMD-2076 exerts its effects through multiple mechanisms of action, including antiproliferative activity and the inhibition of angiogenesis. ENMD-2076 has demonstrated significant, dose-dependent preclinical activity as a single agent, including tumor regression, in multiple xenograft models (e.g. breast, colon, leukemia), as well as activity towards ex vivo-treated human leukemia patient cells. ENMD-2076 has completed a Phase 1 study in patients with solid tumors and is currently in a multi-center Phase 2 study in ovarian cancer as well as Phase 1 studies in multiple myeloma and leukemia. ENMD-2076 has received orphan drug designation from the United States Food and Drug Administration (the “FDA”) for the treatment of ovarian cancer, multiple myeloma and acute myeloid leukemia (“AML”). In the United States, the Orphan Drug Act is intended to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 people in this country. Orphan drug designation provides us with seven years of market exclusivity that begins once ENMD-2076 receives FDA marketing approval. It also provides certain financial incentives that can help support the development of ENMD-2076. See EntreMed's web.