Purity: > 98%
E-3810(cas 1058137-23-7) is a novel dual inhibitor targeting human vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs) with antiangiogenic activity. VEGFR/FGFR dual kinase inhibitor E-3810 inhibits VEGFR-1, -2, -3 and FGFR-1, -2 kinases in the nM range, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death. Both VEGFRs and FGFRs belong to the family of receptor tyrosine kinases that may be upregulated in various tumor cell types.
1. Mol Cell Proteomics. 2014 Jun;13(6):1495-509. doi: 10.1074/mcp.M113.034173. Epub
2014 Apr 2.
Quantitative chemical proteomics identifies novel targets of the anti-cancer
multi-kinase inhibitor E-3810.
Colzani M(1), Noberini R(1), Romanenghi M(2), Colella G(3), Pasi M(4), Fancelli
D(4), Varasi M(4), Minucci S(5), Bonaldi T(6).
(1)From the ‡Department of Experimental Oncology, European Institute of Oncology,
Via Adamello 16, 20139 Milano, Italy; §Center of Genomic Science, Istituto
Italiano di Tecnologia, via Adamello 16, 20139 Milano, Italy;
(2)From the ‡Department of Experimental Oncology, European Institute of Oncology,
Via Adamello 16, 20139 Milano, Italy;
(3)¶EOS S.p.A., Via Monte di Pietà 1/A, 20121 Milano, Italy; ‖Department of
Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale
dei Tumori, Via Amadeo 42, 20133 Milano, Italy;
(4)**Drug Discovery Program, European Institute of Oncology, Via Adamello 16,
20139 Milano, Italy;
(5)From the ‡Department of Experimental Oncology, European Institute of Oncology,
Via Adamello 16, 20139 Milano, Italy; **Drug Discovery Program, European
Institute of Oncology, Via Adamello 16, 20139 Milano, Italy; ‡‡Department of
Bioscience, University of Milan, 20133 Milano, Italy.
(6)From the ‡Department of Experimental Oncology, European Institute of Oncology,
Via Adamello 16, 20139 Milano, Italy; firstname.lastname@example.org.
Novel drugs are designed against specific molecular targets, but almost
unavoidably they bind non-targets, which can cause additional biological effects
that may result in increased activity or, more frequently, undesired toxicity.
Chemical proteomics is an ideal approach for the systematic identification of
drug targets and off-targets, allowing unbiased screening of candidate
interactors in their natural context (tissue or cell extracts). E-3810 is a novel
multi-kinase inhibitor currently in clinical trials for its anti-angiogenic and
anti-tumor activity. In biochemical assays, E-3810 targets primarily vascular
endothelial growth factor and fibroblast growth factor receptors. Interestingly,
E-3810 appears to inhibit the growth of tumor cells with low to undetectable
levels of these proteins in vitro, suggesting that additional relevant targets
exist. We applied chemical proteomics to screen for E-3810 targets by
immobilizing the drug on a resin and exploiting stable isotope labeling by amino
acids in cell culture to design experiments that allowed the detection of novel
interactors and the quantification of their dissociation constant (Kd imm) for
the immobilized drug. In addition to the known target FGFR2 and PDGFRα, which has
been described as a secondary E-3810 target based on in vitro assays, we
identified six novel candidate kinase targets (DDR2, YES, LYN, CARDIAK, EPHA2,
and CSBP). These kinases were validated in a biochemical assay and-in the case of
the cell-surface receptor DDR2, for which activating mutations have been recently
discovered in lung cancer-cellular assays. Taken together, the success of our
strategy-which integrates large-scale target identification and
quality-controlled target affinity measurements using quantitative mass
spectrometry-in identifying novel E-3810 targets further supports the use of
chemical proteomics to dissect the mechanism of action of novel drugs.
2. Mol Cancer Ther. 2013 Feb;12(2):131-40. doi: 10.1158/1535-7163.MCT-12-0275-T.
Epub 2012 Dec 27.
The tyrosine kinase inhibitor E-3810 combined with paclitaxel inhibits the growth
of advanced-stage triple-negative breast cancer xenografts.
Bello E(1), Taraboletti G, Colella G, Zucchetti M, Forestieri D, Licandro SA,
Berndt A, Richter P, D'Incalci M, Cavalletti E, Giavazzi R, Camboni G, Damia G.
(1)Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri,
E-3810 is a novel small molecule that inhibits VEGF receptor-1, -2, and -3 and
fibroblast growth factor receptor-1 tyrosine kinases at nmol/L concentrations
currently in phase clinical II. In preclinical studies, it had a broad spectrum
of antitumor activity when used as monotherapy in a variety of human xenografts.
We here investigated the activity of E-3810 combined with different cytotoxic
agents in a MDA-MB-231 triple-negative breast cancer xenograft model. The
molecule could be safely administered with 5-fluorouracil, cisplatin, and
paclitaxel. The E-3810-paclitaxel combination showed a striking activity with
complete, lasting tumor regressions; the antitumor activity of the combination
was also confirmed in another triple-negative breast xenograft, MX-1. The
activity was superior to that of the combinations paclitaxel+brivanib and
paclitaxel+sunitinib. Pharmacokinetics studies suggest that the extra antitumor
activity of the combination is not due to higher paclitaxel tumor levels, which
in fact were lower in mice pretreated with all three kinase inhibitors, and the
paclitaxel plasma levels excluded reduced drug availability. Pharmacodynamic
studies showed that E-3810, brivanib, and sunitinib given as single agents or in
combination with paclitaxel reduced the number of vessels, but did not modify
vessel maturation. Reduced tumor collagen IV and increased plasma collagen IV,
associated with increased matrix metalloproteinases (MMP), particularly host
MMP-9, indicate a proteolytic remodeling of the extracellular matrix caused by
E-3810 that in conjunction with the cytotoxic effect of paclitaxel on the tumor
cells (caspase-3/7 activity) may contribute to the striking activity of their
combination. These data support the therapeutic potential of combining E-3810
with conventional chemotherapy.
3. Cancer Res. 2011 Feb 15;71(4):1396-405. doi: 10.1158/0008-5472.CAN-10-2700. Epub
2011 Jan 6.
E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor
activity in multiple preclinical models.
Bello E(1), Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC,
D'Incalci M, Cavalletti E, Giavazzi R, Damia G, Camboni G.
(1)Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, and
E.O.S. S.p.A., Milan, Italy.
Tumor angiogenesis is a degenerate process regulated by a complex network of
proangiogenic factors. Existing antiangiogenic drugs used in clinic are
characterized by selectivity for specific factors. Antiangiogenic properties
might be improved in drugs that target multiple factors and thereby address the
inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth
factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate
receptors are key players in promoting tumor angiogenesis. Here we report the
pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF
receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2,
and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range.
Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with
human vascular endothelial cell growth at nanomolar concentrations. In contrast,
E-3810 lacked cytotoxic effects on cancer cell lines under millimolar
concentrations. In a variety of tumor xenograft models, including early- or
late-stage subcutaneous and orthotopic models, E-3810 exhibited striking
antitumor properties at well-tolerated oral doses administered daily. We found
that E-3810 remained active in tumors rendered nonresponsive to the general
kinase inhibitor sunitinib resulting from a previous cycle of sunitinib
treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic
FGF-induced angiogenesis and reduced blood vessel density as assessed by
histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging
analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive
contrast agents after only 5 days of treatment. Taken together, our findings
identify E-3810 as a potent antiangiogenic small molecule with a favorable
pharmacokinetic profile and broad spectrum antitumor activity, providing a strong
rationale for its clinical evaluation.