Home Angiogenesis FLT3 inhibitor ENMD-2076

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ENMD-2076 FLT3 inhibitor

Cat.No.S1181

ENMD-2076 has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25-fold selective for Aurora A than over Aurora B and less potent to RET, SRC, NTRK1/TRKA, CSF1R/FMS, VEGFR2/KDR, FGFR and PDGFRα. This compound inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. Phase 2.
ENMD-2076 FLT3 inhibitor Chemical Structure

Chemical Structure

Molecular Weight: 375.47

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Quality Control

Batch: S118101 DMSO]105 mg/mL]false]Water]1 mg/mL]false]Ethanol]1 mg/mL]false Purity: 99.41%
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99.41

Cell Culture, Treatment & Working Concentration

Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
MV4-11 Function assay Inhibition of CSF-stimulated CSF1R phosphorylation in human MV4-11 cells by immunoblotting method, IC50=0.6μM 29293000
myeloma cells Growth inhibition assay Growth inhibition of in human myeloma cells, IC50=2.99μM 28918096
Click to View More Cell Line Experimental Data

Solubility

In vitro
Batch:

DMSO : 105 mg/mL (279.64 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Water : 1 mg/mL

Ethanol : 1 mg/mL

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Mass Concentration Volume Molecular Weight
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In vivo
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In vivo Formulation Calculator (Clear solution)

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Chemical Information, Storage & Stability

Molecular Weight 375.47 Formula

C21H25N7

 Storage (From the date of receipt)
CAS No. 934353-76-1 Download SDF Storage of Stock Solutions

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

Mechanism of Action

Features
Multi-target, anti-proliferative, pro-apoptotic activity, anti-angiogenic.
Targets/IC50/Ki
FLT3
(Cell-free assay)
1.86 nM
RET
(Cell-free assay)
10.4 nM
Aurora A
(Cell-free assay)
14 nM
VEGFR3/FLT4
(Cell-free assay)
15.9 nM
Src
(Cell-free assay)
20.2 nM
NTRK1/TRKA
(Cell-free assay)
24.2 nM
CSF-1R/c-Fms
(Cell-free assay)
24.8 nM
LCK
(Cell-free assay)
43.7 nM
FAK
(Cell-free assay)
54.9 nM
PDGFRα
(Cell-free assay)
56.4 nM
VEGFR2/KDR
(Cell-free assay)
58.2 nM
BLK
(Cell-free assay)
69.4 nM
FGFR2
(Cell-free assay)
70.8 nM
YES1
(Cell-free assay)
78.4 nM
Abl1 (T315I)
(Cell-free assay)
81.3 nM
FGFR1
(Cell-free assay)
92.7 nM
Fyn
(Cell-free assay)
112 nM
JAK2
(Cell-free assay)
120 nM
Kit
(Cell-free assay)
120 nM
Aurora B
(Cell-free assay)
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. This compound inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM, which induces apoptosis and G2/M phase arrest. It induces regression or complete inhibition of tumor growth in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. This chemical is the L (+) tartrate salt of ENMD-981693. It 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. This compound indicates low cytotoxicity to haematopoietic progenitors. It inhibits the phosphoinositide 3-kinase/Akt pathway and downregulates survivin and X-linked inhibitor of apoptosis. It also inhibits aurora A and B kinases, and induces G2/M cell cycle arrest.
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 this compound concentration are plotted with Grafit and used to calculate IC50 values. Potency of this chemical 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. This compound could prevent the formation of new blood vessels and regress formed vessels in MDA-MB-231 xenograft model. Oral treatment with this chemical (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.
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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