Home Angiogenesis FLT3 inhibitor - Aurora Kinase inhibitor - VEGFR inhibitor ENMD-2076 L-(+)-Tartaric acid

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ENMD-2076 L-(+)-Tartaric acid FLT3 inhibitor

Cat.No.S2018

ENMD-2076 L-(+)-Tartaric acid is the tartaric acid of ENMD-2076, selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold more selective for Aurora A than Aurora B and less potent to VEGFR2/KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.
ENMD-2076 L-(+)-Tartaric acid FLT3 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 525.56

Jump to Mechanism of Action Solubility Chemical Information, Storage & Stability Specificity

Quality Control

Batch: S201801 DMSO]100 mg/mL]false]Water]Insoluble]false]Ethanol]Insoluble]false Purity: 99.36%
99.36

Chemical Information, Storage & Stability

Molecular Weight 525.56 Formula

C25H31N7O6

 Storage (From the date of receipt)
CAS No. 1291074-87-7 -- Storage of Stock Solutions

Synonyms N/A Smiles CC1=CC(=NN1)NC2=CC(=NC(=N2)C=CC3=CC=CC=C3)N4CCN(CC4)C.C(C(C(=O)O)O)(C(=O)O)O

Solubility

In vitro
Batch:

DMSO : 100 mg/mL ( (190.27 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Water : Insoluble

Ethanol : Insoluble

Molarity Calculator

Mass Concentration Volume Molecular Weight

In vivo
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Mechanism of Action

Features
Multi-functional molecule: multi-target, anti-proliferative, pro-apoptotic activity, and anti-angiogenic activity.
Targets/IC50/Ki
FLT3 [1]
1.86 nM
RET [1]
10.4 nM
Aurora A [2]
14 nM
VEGFR3/FLT4 [1]
15.9 nM
Src [1]
20.2 nM
NTRK1/TRKA [1]
24.2 nM
CSF-1R/c-Fms [1]
24.8 nM
LCK [1]
43.7 nM
FAK [1]
54.9 nM
PDGFRα [1]
56.4 nM
VEGFR2/KDR [1]
58.2 nM
BLK [1]
69.4 nM
FGFR2 [1]
70.8 nM
YES1 [1]
78.4 nM
Abl1 (T315I) [1]
81.3 nM
FGFR1 [1]
92.7 nM
Fyn [1]
112 nM
JAK2 [1]
120 nM
Kit [1]
120 nM
Aurora B [2]
350 nM
In vitro
ENMD-2076 indicates activity against multiple kinases involved in angiogenesis, including FLT3, RET, FLT4/VEGFR3, SRC, NTRK1, CSF1R/FMS, LCK, VEGFR2/KDR, FGFR1/2, and PDGFRα with IC50 from 1.86-120 nM. ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025-0.7 μM, which induces apoptosis and G2/M phase arrest. ENMD-2076 induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. [1] ENMD-2076 is the L (+) tartrate salt of ENMD-981693. ENMD-2076 shows significant cytotoxicity against myeloma cell lines (IM9, ARH-77, U266, RPMI 8226, MM.1S, MM.1R, NCI-H929) and primary cells with IC50 from 2.99 to 7.06 μM, which induces apoptosis. ENMD-2076 indicates low cytotoxicity to haematopoietic progenitors. ENMD-2076 inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. ENMD-2076 also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest. [2]
Kinase Assay
Kinase assays
Recombinant Aurora A and B kinase enzymes and appropriate PanVera Z'-Lyte kinase assay kits are purchased. Assays are carried out in kinase assay buffer (50 mM of HEPES, pH 7.5, 10 mM of MgCl2, 5 mM of EGTA, 0.05% Brij-35) supplemented with 2 mM of DTT. Activities are determined at an ATP concentration equivalent to the apparent Km for each enzyme, and an enzyme concentration that results in approximately 30% phosphorylation of the peptide substrate after 1 hour. Dose–response curves of relative enzyme activity versus ENMD-2076 concentration are plotted with Grafit and used to calculate IC50 values. Potency of ENMD-2076 free base against a select panel of 100 kinase enzymes is determined using the SelectScreen kinase profiling service. ATP concentrations are at the apparent Km for each enzyme or 100 μM if the apparent Km could not be reached. Percent inhibition is determined at an ENMD-2076 free base concentration of 1 μM; for kinases where significant inhibition is noted, IC50 values are determined by generating full 10-point dose–response curves.
In vivo
ENMD-2076 has sustained inhibitory effects on the activation of Flt3 as well as VEGFR2/KDR and FGFR1/2 in HT29 xenograft model. ENMD-2076 could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model. [1] Oral treatment with ENMD-2076 (50, 100, 200 mg/kg per day) inhibits the tumour growth in H929 human plasmacytoma xenografts, with significant reduction in phospho-Histone 3 (pH3), Ki-67, and angiogenesis, and also a significant increase in cleaved caspase-3. [2]
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT00904787 Completed
Relapsed or Refractory Hematological Malignancies
CASI Pharmaceuticals Inc.
 April 2009 Phase 1
NCT00806065 Completed
Multiple Myeloma
CASI Pharmaceuticals Inc.
 December 2008 Phase 1
NCT00658671 Completed
Advanced Cancer
CASI Pharmaceuticals Inc.
 April 2008 Phase 1

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