SU 5402

IC50: 0.02, 0.03, 0.51 and > 100 μM for VEGFR2, FGFR1, PDGFRβ and EGFR, respectively

SU 5402 is an inhibitor of VEGF, FGF, and PDGF receptor tyrosine kinases. Receptor tyrosine kinases have been recognized as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, and cardiovascular diseases.

In vitro: SU5402 could inhibit FGFR3 phosphorylation in vitro. B cells dependent on FGFR3 for survival were sensitive to SU5402 specifically. A panel of 11 human myeloma cell lines was studied, among which five beared t(4;14) translocation. The KMS11 human myeloma cell line expressesing constitutively active mutant FGFR3, displayed a 95% increase in G0/G1 cells as well as 45-fold increase in apoptotic cells after SU5402 treatment. In addition, the activated signal-regulated kinases 1 and 2 and signal activator of transcription 3 were down-regulated after SU5402 treatment rapidly. In human myeloma cell lines with wild-type FGFR3, the stimulating effect of aFGF ligand was abrogated by SU5402 [1].

In vivo: BALB/c mice were inoculated with syngeneic pre-B-TD cells and these established tumours were treated with 300 ng/kg SU5402 or carrier alone administered by either direct subcutaneous or intraperitoneal injection. Tumours were collected 24 h later and Western blot analyses indicated a treatment-related decrease in the levels of activated ERK1/2 in the harvested tumors [1].

Clinical trial: N/A

Reference:
[1] Paterson JL,Li Z,Wen XY,Masih-Khan E,Chang H,Pollett JB,Trudel S,Stewart AK.  Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol.2004 Mar;124(5):595-603.

Characterization of SH-SY5Y human neuroblastoma cell growth over glass and SU-8 substrates.[Pubmed:28371423]

J Biomed Mater Res A. 2017 Aug;105(8):2129-2138.

The physical properties of substrates can have profound effects on the structure and function of cultured cells. In this study, we aimed to examine the viability, adherence, and morphological and functional variations between SH-SY5Y human neuroblastoma cells cultured on SU-8 surfaces compared with control surfaces composed of borosilicate glass, which are routinely used for cell culture. The SU-8 polymer has been extensively studied for its biocompatibility, but there has been little investigation into the characteristic differences between cells cultured on SU-8 when compared with glass. SH-SY5Y cells were cultured within polydimethylsiloxane wells on both SU-8 and glass substrates for up to 72 h after which flow cytometry and enzyme-linked immunosorbent assay analysis was performed to examine cell viability and neurotoxicity. Immunocytochemistry was also performed to analyze the morphological and functional characteristics of the cells. Atomic force microscopy was performed to measure surface roughness and to map cell-substrate interactions. Nanoindentation testing was used to characterize the mechanical properties of polymer surface. Results showed that SH-SY5Y cells grown on SU-8 have significantly improved viability and increased morphological and functional characteristics of neurodevelopment. The results from this study suggest that the mechanical properties of the polymer are optimal for the study of cultured cell lines, which could account for the increased viability, adherence, and morphological and functional characteristics of neurodevelopment. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2129-2138, 2017.

Likelihood analysis of supersymmetric SU(5) GUTs.[Pubmed:28260982]

Eur Phys J C Part Fields. 2017;77(2):104.

We perform a likelihood analysis of the constraints from accelerator experiments and astrophysical observations on supersymmetric (SUSY) models with SU(5) boundary conditions on soft SUSY-breaking parameters at the GUT scale. The parameter space of the models studied has seven parameters: a universal gaugino mass [Formula: see text], distinct masses for the scalar partners of matter fermions in five- and ten-dimensional representations of SU(5), [Formula: see text] and [Formula: see text], and for the [Formula: see text] and [Formula: see text] Higgs representations [Formula: see text] and [Formula: see text], a universal trilinear soft SUSY-breaking parameter [Formula: see text], and the ratio of Higgs vevs [Formula: see text]. In addition to previous constraints from direct sparticle searches, low-energy and flavour observables, we incorporate constraints based on preliminary results from 13 TeV LHC searches for jets + [Formula: see text] events and long-lived particles, as well as the latest PandaX-II and LUX searches for direct Dark Matter detection. In addition to previously identified mechanisms for bringing the supersymmetric relic density into the range allowed by cosmology, we identify a novel [Formula: see text] coannihilation mechanism that appears in the supersymmetric SU(5) GUT model and discuss the role of [Formula: see text] coannihilation. We find complementarity between the prospects for direct Dark Matter detection and SUSY searches at the LHC.

Promotion and guidance of neural network formation on SU-8 photoresist microchannels adjusted with multilayer films.[Pubmed:28269265]

Conf Proc IEEE Eng Med Biol Soc. 2016 Aug;2016:4447-4450.

Induction of neural stem/progenitor cells (NSPCs) and establishment of neural network are important issues on neural engineering. In this work, a platform was designed to control and evaluate the differentiation of NSPCs, neurite direction, and to promote the neurite outgrowth. Polyelectrolyte multilayer (PEM) films provide surface properties by and have been used to regulate NSPCs differentiation in our previous study. Herein, a culture platform composed of SU-8 microchannel and PEM films was designed to achieve the goal of promoting NSPCs differentiation and to evaluate the effect of PEM films on the guidance of neural network formation. In this culture platform, NSPCs were induced into functional neurons, and neural network formation was accomplished on ITO glass-PEM films successfully.

Prospective association between adherence to the Mediterranean diet and risk of depressive symptoms in the French SU.VI.MAX cohort.[Pubmed:28283824]

Eur J Nutr. 2018 Apr;57(3):1225-1235.

PURPOSE: This study examines whether adherence to the Mediterranean Diet (MD) measured by several dietary indexes was associated with incident depressive symptoms in a large French cohort. METHODS: The study sample consisted of 3523 participants from the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort who had at least three dietary records at baseline during the first 2 years of follow-up (1994-1996), free of depression at the beginning of the study (1996-1997) and available Center for Epidemiologic Studies Depression Scale (CES-D) data at the end of follow-up (2007-2009). The rMED was computed. Incident depressive symptoms were defined by a CES-D score >/=17 for men and >/=23 for women in 2007-2009. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using multivariable logistic regression models. Several sensitivity analyses were performed. RESULTS: In the present study, 172 incident cases of depressive symptoms were identified during the follow-up (mean = 12.6 years). After adjustment for a wide range of potential confounders, adherence to the rMED score (continuous variable) was significantly associated with incident depressive symptoms in men (OR 0.91; 95% CI 0.83-0.99; p = 0.03), but not in women. Use of the Literature-Based Adherence Score to the Mediterranean Diet (LAMD) and the classic MD score (MDS) provide similar findings. CONCLUSIONS: In the current study, higher adherence to the Mediterranean Diet at midlife was associated with a lower risk of incident depressive symptoms, particularly in men, increasing scientific evidence for a beneficial role of Mediterranean Diet on health. Further investigations in particular among women are needed.

Neural stem cell differentiation is mediated by integrin beta4 in vitro.[Pubmed:18834954]

Int J Biochem Cell Biol. 2009 Apr;41(4):916-24.

Neural stem cells are capable of differentiating into three major neural cell types, but the underlying molecular mechanisms remain unclear. Here, we investigated the mechanism by which integrin beta4 modulates mouse neural stem cell differentiation in vitro. Inhibition of endogenous integrin beta4 by RNA interference inhibited the cell differentiation and the expression of fibroblast growth factor receptor 2 but not fibroblast growth factor receptor 1 or fibroblast growth factor receptor 3. Overexpression of integrin beta4 in neural stem cells promoted neural stem cell differentiation. Furthermore, integrin beta4-induced differentiation of neural stem cells was attenuated by SU5402, the inhibitor of fibroblast growth factor receptors. Finally, we investigated the role of integrin beta4 in neural stem cell survival: knockdown of integrin beta4 did not affect survival or apoptosis of neural stem cells. These data provide evidence that integrin beta4 promotes differentiation of mouse neural stem cells in vitro possibly through fibroblast growth factor receptor 2.

FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination.[Pubmed:15889083]

Nature. 2005 May 12;435(7039):172-7.

The precise specification of left-right asymmetry is an essential process for patterning internal organs in vertebrates. In mouse embryonic development, the symmetry-breaking process in left-right determination is initiated by a leftward extraembryonic fluid flow on the surface of the ventral node. However, it is not known whether the signal transduction mechanism of this flow is chemical or mechanical. Here we show that fibroblast growth factor (FGF) signalling triggers secretion of membrane-sheathed objects 0.3-5 microm in diameter termed 'nodal vesicular parcels' (NVPs) that carry Sonic hedgehog and retinoic acid. These NVPs are transported leftward by the fluid flow and eventually fragment close to the left wall of the ventral node. The silencing effects of the FGF-receptor inhibitor SU5402 on NVP secretion and on a downstream rise in Ca2+ were sufficiently reversed by exogenous Sonic hedgehog peptide or retinoic acid, suggesting that FGF-triggered surface accumulation of cargo morphogens may be essential for launching NVPs. Thus, we propose that NVP flow is a new mode of extracellular transport that forms a left-right gradient of morphogens.

Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma.[Pubmed:14871245]

Br J Haematol. 2004 Mar;124(5):595-603.

Dysregulation of fibroblast growth factor receptor 3 (FGFR3) by the translocation t(4;14)(p16;q32) occurs in 15% of multiple myeloma (MM) patients and confers a growth and survival advantage to malignant plasma cells. As FGFR3 is a molecular target, we assessed the therapeutic potential of the FGFR-specific tyrosine kinase inhibitors SU5402 and SU10991 in MM. SU5402 inhibited FGFR3 phosphorylation in vitro and in murine MM tumour models. B cells dependent on FGFR3 for survival were specifically sensitive to SU5402. A panel of 11 human myeloma cell lines was studied, five bearing the t(4;14) translocation. The KMS11 human myeloma cell line, which expresses constitutively active mutant FGFR3, displayed an 85% decrease in S-phase cells, a 95% increase in G0/G1 cells, and 4.5-fold increase in apoptotic cells after 72 h treatment with 10 micromol/l SU5402. Activated extracellular signal-regulated kinases 1 and 2 and signal transducer and activator of transcription 3 were rapidly down-regulated after SU5402 treatment. In human myeloma cell lines expressing wild-type FGFR3 the stimulating effect of aFGF ligand was abrogated by SU5402 treatment. Myeloma cells lacking the t(4;14) or with the t(4;14) and a secondary RAS mutation did not respond to therapy. These findings support the development of clinical trials of early intervention with FGFR3 inhibitors in t(4;14) myeloma.

Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases.[Pubmed:10602697]

J Med Chem. 1999 Dec 16;42(25):5120-30.

Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain-containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC(50) values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC(50) values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC(50) value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.

SU 5402 is a potent multi-targeted receptor tyrosine kinase inhibitor with IC50 of 20 nM, 30 nM, and 510 nM for VEGFR2, FGFR1, and PDGFRβ, respectively.

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