Search results for "target"
showing 10 items of 1196 documents
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
2018
Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformati…
Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study.
2018
Abstract Introduction Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. Aim To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methods Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th–75th IQR). Results Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3…
A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening
2018
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Pharmacokinetics of a sustained release formulation of PDGFβ-receptor directed carrier proteins to target the fibrotic liver
2018
Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGF beta R that is highly upregulated on a…
PI3K inhibition reduces murine and human liver fibrogenesis in precisioncut liver slices
2019
Background: Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).Methods: Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 mu M for 48 h. PI3K pathway act…
In Vivo siRNA Delivery to Immunosuppressive Liver Macrophages by alpha-Mannosyl-Functionalized Cationic Nanohydrogel Particles
2020
Macrophages are the front soldiers of the innate immune system and are vital for immune defense, tumor surveillance, and tissue homeostasis. In chronic diseases, including cancer and liver fibrosis, macrophages can be forced into an immunosuppressive and profibrotic M2 phenotype. M2-type macrophages overexpress the mannose receptor CD206. Targeting these cells via CD206 and macrophage repolarization towards an immune stimulating and antifibrotic M1 phenotype through RNA interference represents an appealing therapeutic approach. We designed nanohydrogel particles equipped with mannose residues on the surface (ManNP) that delivered siRNA more efficiently to M2 polarized macrophages compared t…
The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer
2016
Abstract: Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation. Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in e…
Targeting BRAF and RAS in Colorectal Cancer
2021
Simple Summary In colorectal cancer, mutations of the KRAS and BRAF genes are quite common and can contribute to the activation of cell signaling pathways that lead to cell proliferation and differentiation. These processes promote cancer growth, and in some cases, they may cause cells to develop resistance to certain types of treatment, notably EGFR inhibitors. We summarize recent knowledge regarding the effects of KRAS and BRAF mutations in the setting of colorectal cancer and discuss the new therapies under development. Abstract Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the …
RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma
2019
Introduction: Hepatocellular carcinoma (HCC) is a significant problem globally because of viral infections and the increasing incidence of obesity and fatty liver disease. However, it is difficult to treat because its inherent genetic heterogeneity results in activation of numerous signaling pathways. Kinases have been targeted for decades with varying results, but the development of therapeutic resistance is a major challenge. Areas covered: The key roles of the RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1, TP53 microRNAs (miRs) as therapeutic targets are discussed and we suggests novel approaches for targeting miRs or their downstream targets to combat HCC. We performed literature searches using…
Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity—Diverse effects on cell growth, metabolism and cancer
2016
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple sign…