Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells

Angelucci, Adriano; Schenone, Silvia; Gravina, Giovanni Luca; Muzi, Paola; Festuccia, Claudio; Vicentini, Carlo; Botta, Maurizio; Bologna, Mauro

doi:10.1016/j.ejca.2006.06.024

Cited by 64 publications

(59 citation statements)

References 24 publications

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“…Dasatinib, for instance, is known to inhibit platelet-derived growth factor receptor β, Abl, c-Kit and EphA2 (28). Although previous studies have shown that Src inhibitors may affect proliferation of prostate cancer cells, the concentrations required to elicit this effect considerably exceeded those needed to suppress adhesion and migration (10,12). In a recent publication, it has been shown that dasatinib inhibited proliferation of both LNCaP and PC-3MM2GL cell line with dasatinib concentrations >100 nmol/L (14).…”

Section: Discussionmentioning

confidence: 94%

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Tatarov

Mitchell

Seywright

et al. 2009

Clinical Cancer Research

141

130

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Purpose: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there are no studies relating SFK activation to patient survival. This study was designed to determine if SFK activation was up-regulated with the development of AIPC and if patients could be selected who were more likely to respond to therapy. Experimental Design: A unique cohort of matched prostate tumor samples, taken before hormone deprivation therapy and following hormone relapse, was used to determine by immunohistochemistry on an individual patient basis if SFK activity changed with progression to AIPC and whether this related to patient outcome measures. Using matched, hormone-sensitive and hormone-refractory cell lines, we determined if hormone status affected the way prostate cancer cells respond to suppression of SFK activity by the small-molecule inhibitor dasatinib.Results: In the current study, 28% of patients with AIPC exhibited an increase in SFK activity in prostate cancer tissue, these patients had significantly shorter overall survival (P < 0.0001), and activated SFK expression correlated with the presence of distant metastases. Dasatinib inhibited phosphorylation of Src and Lyn and the downstream substrate FAK in hormone-sensitive and hormone-refractory cell lines. Although migration was reduced by dasatinib in both cell lines, proliferation of hormone-refractory cells only was inhibited. Conclusion: Appropriate patient selection may allow better targeting of prostate cancer patients who are likely to respond to the treatment with SFK inhibitors at the same time improving the outcome of clinical trials.Prostate cancer is the most common cancer in men and is the second leading cause of cancer-related deaths in men in the United States and United Kingdom (1). Treatment options for locally advanced and metastatic prostate cancer are limited to androgen deprivation therapy or surgical castration. Unfortunately, nearly all of these patients eventually develop androgenindependent prostate cancer (AIPC) for which currently there are no established effective therapies.Our understanding of the mechanisms involved in the development of AIPC has considerably improved over the last decade. When deprived of androgen stimulation, androgensensitive prostate cancer (ASPC) cells develop the ability to survive and thrive by up-regulating oncogenic pathways where tyrosine kinases often play a crucial role (2). The nonreceptor tyrosine kinase Src is thought to facilitate the interaction between intracellular molecular cascades as well as form complexes with the androgen receptor (AR), which is expressed by the majority of AIPC cells. Tyrosine phosphorylation is an important factor in the regulation of AR activity resulting in translocation of the receptor into the nucleus and increase in DNA synthesis. Src activation by growth factors in prostate cancer cells has been shown to correlate with AR tyrosine phosphorylation, especially under androgen-depleted condi...

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Section: Discussionmentioning

confidence: 94%

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Tatarov

Mitchell

Seywright

et al. 2009

Clinical Cancer Research

141

130

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“…2 This hormonal therapy is initially efficient, although the majority of patients will subsequently become unresponsive to androgen inhibition 45 and consequently the development of AIPC is a clinical problem of major concern. 2,3 In fact, AIPC is a complex and heterogeneous form of PC with a high capacity of progression and metastization.…”

Section: Discussionmentioning

confidence: 99%

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility

et al. 2009

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Proliferative mechanisms involving the epidermal growth factor (EGF) and transforming growth factor beta (TGF-b 1 ) ligands are potential alternative pathways for prostate cancer (PC) progression to androgen independence (AI). Thus, the combined effect of EGF and TGFB1 functional polymorphisms might modulate tumor microenvironment and consequently its development. We studied EGF þ 61G4A and TGFB1 þ 869T4C functional polymorphisms in 234 patients with PC and 243 healthy individuals. Intermediate-and highproliferation genetic profile carriers have increased risk for PC (odds ratio (OR) ¼ 3.76, P ¼ 0.007 and OR ¼ 3.98, P ¼ 0.004, respectively), when compared with low proliferation individuals. Multivariate analysis showed a significantly lower time to AI in the high proliferation group, compared with the low/intermediate proliferation genetic profile carriers (HR ¼ 2.67, P ¼ 0.039), after adjustment for age, metastasis and stage. Results suggest that combined analysis of target genetic polymorphisms may contribute to the definition of cancer susceptibility and pharmacogenomic profiles. Combined blockage of key molecules in proliferation signaling pathways could be one of the most promising strategies for androgen-independent prostate cancer.

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“…agents is limited due to the rapidly developing drug resistance in conjunction with the unsatisfactory status of present treatments of bacterial and fungal infections [3,4]. Pyrimidine nucleus has gained potential importance in medicinal chemistry, as some of its derivatives exhibited a wide range of biological activities, such as antiviral [5][6][7][8], anticoccidials [9,10], antimicrobial [11][12][13][14], antitumor [15][16][17][18], herbicidal, antileukemic [19,20], pesticides [21], CNS agents [22], tuberculostatic [23][24][25], antileishmanial [26][27][28], radioprotectant [29], anti-in ammatory [30], and cardiovascular activities [31,32]. The biological signicance of the above heterocycle prompted us to explore the synthesis of novel pyrimidines from 3-amino-2-methyl-5,6, 7,8-tetrahydrobenzo [4,5] The asymmetric unit of the title compound contains one independent molecule.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of N,N-dimethyl-N′-(2-methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)formimidamide, C₁₄H₁₈N₄OS

Aljaeed

Lahsasni

Ghabbour

et al. 2017

Zeitschrift Für Kristallographie - New Crystal Structures

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C14H 18 N4OS, monoclinic, P21/c (no. 14), a = 15.479(4) Å, b = 13.203(3) Å, c = 7.3147(17) Å, β = 99.385(7)°, V = 1474.9(6) Å 3 , CCDC no.: 1486095The asymmetric unit of the title crystal structure is shown in the gure. Tables 1 and 2 contain details on crystal structure and measurement conditions and a list of the atoms including atomic coordinates and displacement parameters. Source of materialA mixture of 3-amino-2-methyl-5, 6,7,8-tetrahydrobenzo[4,5] thieno [2,3-d]pyrimidin-4(3H)-one (0.2 g, 1 mmol), and N,

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Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells

Cited by 64 publications

References 24 publications

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility

Crystal structure of N,N-dimethyl-N′-(2-methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)formimidamide, C₁₄H₁₈N₄OS

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Pyrazolo[3,4-d]pyrimidines c-Src inhibitors reduce epidermal growth factor-induced migration in prostate cancer cells

Cited by 64 publications

References 24 publications

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Combined analysis of EGF+61G>A and TGFB1+869T>C functional polymorphisms in the time to androgen independence and prostate cancer susceptibility

Crystal structure of N,N-dimethyl-N′-(2-methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)formimidamide, C14H18N4OS

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Crystal structure of N,N-dimethyl-N′-(2-methyl-4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-3(4H)-yl)formimidamide, C₁₄H₁₈N₄OS