Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors:  4-(Phenylamino)pyrazolo[3,4-<i>d</i>]pyrimidines

Traxler, Peter; Bold, Guido; Frei, Joerg; Lang, Marc; Lydon, Nicholas B.; Mett, Helmut; Buchdunger, Elisabeth; Meyer, Thomas; Mueller, Marcel; Furet, Pascal

doi:10.1021/jm970124v

Cited by 196 publications

(155 citation statements)

References 33 publications

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“…Interestingly PP3, which we initially used as a control for PP2, also blocked the SOCS2-induced neurite outgrowth (Fig. 3D); however, PP3 is an ATP analogue that is also an EGFR inhibitor (25). Addition of the EGFR inhibitor AG490 also blocked SOCS2-induced neurite outgrowth (data not shown).…”

Section: Socs2 Enhances Neurite Outgrowth In Central Nervousmentioning

confidence: 83%

SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

Goldshmit

Walters

Scott

et al. 2004

Journal of Biological Chemistry

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Suppressor of cytokine signaling (SOCS) 2 is a negative regulator of growth hormone (GH) signaling that regulates body growth postnatally and neuronal differentiation during development. SOCS2 binds to the GH receptor and inhibits GH signaling, including attenuation of STAT5 activation. Here we describe a new function and mechanism of action for SOCS2. Overexpression of SOCS2 in central nervous system neurons promoted neurite outgrowth, and in PC12 cells, neurite outgrowth was induced under nondifferentiating conditions, leading to inhibition of the neurite-inhibitory GTPase Rho and activation of the neurite-promoting GTPase Rac1. Addition of the epidermal growth factor receptor (EGFR) inhibitors PP3 or AG490 or the Src kinase inhibitor PP2 blocked the SOCS2-induced neurite outgrowth. The overexpressed SOCS2 bound to the EGFR, which was constitutively phosphorylated at Tyr 845 , the Src binding site. Overexpression of the phosphatase SHP-2 reduced the constitutive EGFR phosphorylation and subsequent neurite outgrowth. SOCS2 expression also resulted in a modest 30% decrease in phosphorylation of STAT5b at Tyr 699 , which is the primary site on STAT5 phosphorylated by GH; however, total tyrosine phosphorylation of STAT5 was decreased by 75-80% under basal and epidermal growth factorstimulated conditions. Our findings suggest that SOCS2 regulates EGFR phosphorylation, leading to regulation of neurite outgrowth through a novel pathway that is distinct from GH.

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Section: Socs2 Enhances Neurite Outgrowth In Central Nervousmentioning

confidence: 83%

SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

Goldshmit

Walters

Scott

et al. 2004

Journal of Biological Chemistry

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“…7a). These effects were dependent on the dose of PP2 and were not seen in the presence of PP3, which served as a negative control (18) (Fig. 7, b and d).…”

Section: Il-6-induced Tyrosine Phosphorylation Of Gab1 and Gab2 In MMmentioning

confidence: 93%

“…Kinase Inhibitors-The pyrazolopyrimidine PP2, a potent inhibitor of Src family tyrosine kinases (17), and PP3, a negative control for PP2 (18), were obtained from Calbiochem-Novabiochem (San Diego, CA). PP2 and PP3 were dissolved in dimethyl sulfoxide (Me 2 SO) and stored as 5 mM stock solutions at Ϫ20°C.…”

Section: Methodsmentioning

confidence: 99%

Critical Role for Hematopoietic Cell Kinase (Hck)-mediated Phosphorylation of Gab1 and Gab2 Docking Proteins in Interleukin 6-induced Proliferation and Survival of Multiple Myeloma Cells

Podar

Mostoslavsky

Sattler

et al. 2004

Journal of Biological Chemistry

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Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma via activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling cascade. In this report we show that Grb2-associated binder (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma cells; and that interleukin-6 induces their tyrosine phosphorylation and association with downstream signaling molecules. We further demonstrate that these events are Src family tyrosine kinase-dependent and specifically identify the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein kinase. Conversely, inhibition of Src family tyrosine kinases by the pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1, leading to significant reduction of multiple myeloma cell proliferation and survival. Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma. 1 is a potent growth and survival factor in multiple myeloma (MM) initiating signaling pathways via binding to the IL-6 receptor. Early IL-6 signaling events that ultimately lead to the activation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K) are poorly understood. The IL-6 receptor is composed of two ␣-chains (IL-6 receptor ␣, gp80, 80 kDa), which are the binding molecules, and two ␤-chains (gp130, 130 kDa), which are the signal transducers. IL-6 binding to its receptor triggers both the association of IL-6R␣ with gp130 and gp130 phosphorylation. The binding and activation of Src homology-containing tyrosine phosphatase (SHP)-2 and signal transducer and activator of transcription (STAT) 3 are dependent on the phosphorylation of cytoplasmic gp130 domain residues Tyr-759 and Tyr-767, Tyr-814, Tyr-905, and Tyr-915, respectively (1, 2). Hematopoietic cell kinase (Hck) is a member of the highly conserved Src family of protein-tyrosine kinases (SFKs), which mediate mitogenesis, differentiation, survival, migration, and adhesion (3). In contrast to the ubiquitous expression pattern of Src, Yes, and Fyn, the expression of Hck is restricted to the hematopoietic system; specifically, Hck is preferentially expressed in hematopoietic cells of the myeloid and B-lymphoid lineages (4, 5). In B-lymphoid lineages Hck is a common feature of pro-B-cells and its expression decreases with B-cell differentiation (6). Importantly, Hck binds to an "acidic" domain comprising amino acids 771-811 of gp130 and is independent of STAT3 and SHP2 association via tyrosine residues 759, 767, and 814. Functionally, this region is responsible for the activation of Hck and subsequently for the phosphorylation of ERK and the dephosphorylation of Pyk2, therefore mediating cell prolif...

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“…One of these privileged scaffold is the pyrazolo [3,4-d]pyrimidine nucleus, which proved to be a useful core for a variety of ATP-competitive TK inhibitors. Compounds belonging to this structural chemotype have been described as potent inhibitors of either cytoplasmatic TKs, such as cSrc and Abl [16][17][18][19][20][21] or receptor TKs, in particular EGFR [22].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

Bocci¹,

Fioravanti²,

Motta³

et al. 2011

Biochemical Pharmacology

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Aims. To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumour cells and to show its mechanism of action.Methods. Proliferation and apoptotic assays were performed on microvascular endothelial (HMVECd) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Conclusions.The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cell cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signalling pathways.

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Use of a Pharmacophore Model for the Design of EGF-R Tyrosine Kinase Inhibitors: 4-(Phenylamino)pyrazolo[3,4-d]pyrimidines

Cited by 196 publications

References 33 publications

SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

SOCS2 Induces Neurite Outgrowth by Regulation of Epidermal Growth Factor Receptor Activation

Critical Role for Hematopoietic Cell Kinase (Hck)-mediated Phosphorylation of Gab1 and Gab2 Docking Proteins in Interleukin 6-induced Proliferation and Survival of Multiple Myeloma Cells

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

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