Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells

Radi, Marco; Brullo, Chiara; Crespan, Emmanuele; Tintori, Cristina; Musumeci, Francesca; Biava, Mariangela; Schenone, Silvia; Dreassi, Elena; Zamperini, Claudio; Maga, Giovanni; Pagano, Dafne; Angelucci, Adriano; Bologna, Mauro; Botta, Maurizio

doi:10.1016/j.bmcl.2011.07.079

Cited by 47 publications

(60 citation statements)

References 33 publications

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“…Furthermore, the incorporation of the aminopyrazole scaffold into condensed heterocycles has emerged as a powerful strategy for novel anticancer drug development. Numerous pyrazolo[1,5‐ a ]pyrimidines, pyrazolo[3,4‐ d ]pyrimidines, pyrazolo[1,5‐ a ][1,3,5]‐triazines, pyrazolo[5,1‐ c ][1,2,4]triazoles, and other aminopyrazole‐fused bicycles display remarkable cancer‐related enzyme inhibitory activities. Despite several synthetic routes are available for the construction of imidazo[1,2‐ b ]pyrazoles, their pharmacological properties are barely studied, and only a limited number of reports focused on their antitumor potential .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

Demjén

Alföldi²,

Angyal

et al. 2018

Archiv der Pharmazie

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The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure-activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC = 0.183 μM).

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Section: Introductionmentioning

confidence: 99%

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

Demjén

Alföldi²,

Angyal

et al. 2018

Archiv der Pharmazie

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“…TrkB signaling is known to contribute to the aggressive nature of these poor-prognosis tumors and constitutively active TrkB demonstrates malignant transformation potential [20,21]. The non-receptor tyrosine kinases Src and focal adhesion kinase (FAK) have also been implicated in high-risk neuroblastoma biology [22,23]. More recently, the DNA damage response protein (DDR) checkpoint kinase 1 (Chk1) has been identified as being overactive in neuroblastoma.…”

Section: Introductionmentioning

confidence: 99%

Quantitative Phosphoproteomic Analysis Identifies Activation of the RET and IGF-1R/IR Signaling Pathways in Neuroblastoma

DeNardo

Holloway

et al. 2013

PLoS ONE

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Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10), modeling a resistant tumor, and a human neural precursor cell line (NPC), modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK) phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR), and fibroblast growth factor receptor 1 (FGFR1). Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis.

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“…Among the members of this library, compound SI214 ( Figure 1a) is a potent Src inhibitor (K i = 90 nM) and possesses a considerable antiproliferative effect on the SH-SY5Y Neuroblastoma cell line (IC 50 = 80 nM). Despite these promising biological data, SI214 has low solubility in water (0.12 g/mL), which prevents its oral administration [21]. It has been successfully demonstrated that solid dispersions of pyrazolo [3,4-d]pyrimidine analogous containing an hydrophilic polymer as inert carrier possess an increased apparent water solubility due to enhanced interactions between the hydrophilic polymeric chain and the hydrophobic drug scaffold leading.…”

Section: Introductionmentioning

confidence: 99%

Starch/Poly(glycerol-adipate) Nanocomposites: A Novel Oral Drug Delivery Device

et al. 2020

Self Cite

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Biocompatible and bio-based materials are an appealing resource for the pharmaceutical industry. Poly(glycerol-adipate) (PGA) is a biocompatible and biodegradable polymer that can be used to produce self-assembled nanoparticles (NPs) able to encapsulate active ingredients, with encouraging perspectives for drug delivery purposes. Starch is a versatile, inexpensive, and abundant polysaccharide that can be effectively applied as a bio-scaffold for other molecules in order to enrich it with new appealing properties. In this work, the combination of PGA NPs and starch films proved to be a suitable biopolymeric matrix carrier for the controlled release preparation of hydrophobic drugs. Dynamic Light Scattering (DLS) was used to determine the size of drug-loaded PGA NPs, while the improvement of the apparent drug water solubility was assessed by UV-vis spectroscopy. In vitro biological assays were performed against cancer cell lines and bacteria strains to confirm that drug-loaded PGA NPs maintained the effective activity of the therapeutic agents. Dye-conjugated PGA was then exploited to track the NP release profile during the starch/PGA nanocomposite film digestion, which was assessed using digestion models mimicking physiological conditions. The collected data provide a clear indication of the suitability of our biodegradable carrier system for oral drug delivery.

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Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells

Cited by 47 publications

References 33 publications

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2‐b]pyrazole‐7‐carboxamides

Quantitative Phosphoproteomic Analysis Identifies Activation of the RET and IGF-1R/IR Signaling Pathways in Neuroblastoma

Starch/Poly(glycerol-adipate) Nanocomposites: A Novel Oral Drug Delivery Device

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