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| http://dx.doi.org/10.1038/bcj.2016.106 | DOI Listing |
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Establishing a physiologically based pharmacokinetic framework for aldehyde oxidase and dual aldehyde oxidase-CYP substrates.
CPT Pharmacometrics Syst Pharmacol
January 2025
Centre for Applied Pharmacokinetic Research, The University of Manchester, Manchester, UK.
Aldehyde oxidase (AO) contributes to the clearance of many approved and investigational small molecule drugs, which are often dual substrates of AO and drug-metabolizing enzymes such as cytochrome P450s (CYPs). As such, the lack of established framework for quantitative translation of the clinical pharmacologic correlates of AO-mediated clearance represents an unmet need. This study aimed to evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling in the development of AO and dual AO-CYP substrates.
View Article and Find Full Text PDFPI3Kδ activation, IL-6 overexpression, and CD37 loss cause resistance to naratuximab emtansine in lymphomas.
Blood Adv
December 2024
Institute of Oncology Research, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.
Article Synopsis
- CD37-targeted therapies, like naratuximab emtansine, have shown promise in treating lymphoma, demonstrating strong anti-tumor activity both alone and when combined with rituximab.
- The study investigated 54 lymphoma models, revealing that the drug's effectiveness varied with CD37 expression and discovered mechanisms of resistance related to genetic changes in cancer cells.
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A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon.
Neoplasia
November 2024
BeiGene Global Research, Beijing 102206, PR China. Electronic address:
PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with ICs ranging from 1.
View Article and Find Full Text PDFPI3K Inhibitors in Hematology: When One Door Closes….
Clin Cancer Res
September 2024
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies.
View Article and Find Full Text PDFPegylated-liposomes increase the efficacy of Idelalisib in lymphoma B-cells.
Int J Pharm
May 2024
Dept. of Scienze della Vita e dell'Ambiente, Sezione di Scienze del Farmaco, University of Cagliari, S.P. Monserrato-Sestu Km 0.700, 09042 Monserrato, (Cagliari), Italy. Electronic address:
New drugs and technologies are continuously developed to improve the efficacy and minimize the critical side effects of cancer treatments. The present investigation focuses on the development of a liposomal formulation for Idelalisib, a small-molecule kinase inhibitor approved for the treatment of lymphoid malignancies. Idelalisib is a potent and selective antitumor agent, but it is not indicated nor recommended for first-line treatment due to fatal and serious toxicities.
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