Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma (HCC). Here, we report that Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) is a major target of sorafenib and generates a series of sorafenib derivatives to search for potent SHP-1 agonists that may act as better anti-HCC agents than sorafenib. Sorafenib increases SHP-1 activity by direct interaction and impairs the association between the N-SH2 domain and the catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of the N-SH2 domain (dN1) or point mutation (D61A) of SHP-1 abolished the effect of sorafenib on SHP-1, phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and apoptosis, suggesting that sorafenib may affect SHP-1 by triggering a conformational switch relieving its autoinhibition. Molecular docking of SHP-1/sorafenib complex confirmed our findings in HCC cells. Furthermore, novel sorafenib derivatives SC-43 and SC-40 displayed more potent anti-HCC activity than sorafenib, as measured by enhanced SHP-1 activity, inhibition of p-STAT3, and induction of apoptosis. SC-43 induced substantial apoptosis in sorafenib-resistant cells and showed better survival benefits than sorafenib in orthotopic HCC tumors.CONCLUSIONIn this study, we identified SHP-1 as a major target of sorafenib. SC-43 and SC-40, potent SHP-1 agonists, showed better anti-HCC effects than sorafenib in vitro and in vivo. Further clinical investigation is warranted.

01 May 1989·Pharmacology Biochemistry and BehaviorQ4 · PSYCHOLOGY

Comparison of oral and subcutaneous routes of cocaine administration on behavior, plasma drug concentration and toxicity in female rats

Q4 · PSYCHOLOGY

Article

Author: Fico, T A ; Dow-Edwards, D ; Osman, M ; Hutchings, D E ; Gamagaris, Z

Oral and subcutaneous routes of administration of cocaine HCl were investigated in female Wistar rats for food and water consumption, locomotor activity, stereotypic behaviors, plasma drug concentrations and injection site pathology. Animals received either 40 or 80 mg/kg/day by gastric intubation (PO-40 and PO-80 respectively) or 20 or 40 mg/kg/day subcutaneously (SC-20 and SC-40). All groups received the drug or the vehicle for 16 consecutive days. Locomotor activity and stereotypy were evaluated on Days 1, 5, 10, and 15. Plasma drug concentrations and injection site pathology were determined on Day 16. Subcutaneous administration was associated with a sensitization to the effects of cocaine on locomotion and stereotypy, higher blood levels than oral administration at the same dose, and severe dermal lesions. However, there were no differences in any measure between the SC-20 and SC-40 groups. Oral cocaine was also associated with behavioral sensitization. However, unlike the SC route, oral cocaine was characterized by dose-related increases in locomotion and stereotypy in the absence of gastrointestinal pathology. Inasmuch as oral administration resulted in dose-response relationships and low toxicity while subcutaneous administration did not, these factors should be considered in future studies utilizing chronic cocaine administration.

Foods

Encapsulation of Rich-Carotenoids Extract from Guaraná (Paullinia cupana) Byproduct by a Combination of Spray Drying and Spray Chilling

Article

Author: Campanella, Osvaldo H. ; da Costa Rodrigues, Christianne Elisabete ; Pinho, Lorena Silva ; Favaro-Trindade, Carmen Sílvia ; de Sá, Samuel Henrique Gomes ; Chen, Da ; de Lima, Priscilla Magalhães

Guaraná byproducts are rich in carotenoids, featuring strong antioxidant capacity and health-promoting benefits. However, these compounds are highly susceptible to oxidation and isomerization, which limits their applications in foods. This research aimed to encapsulate the carotenoid-rich extract from reddish guaraná peels by spray drying (SD), chilling (SC), and their combination (SDC) using gum arabic and vegetable fat as carriers. The carotenoid-rich extract was analyzed as a control, and the formulations were prepared with the following core–carrier ratios: SD20 (20:80), SD25 (25:75), SD33 (33:67), SC20 (20:80), SC30 (30:70), SC40 (40:60), SDC10 (10:90), and SDC20 (20:80). The physicochemical properties of the formed microparticles were characterized, and their storage stability was evaluated over 90 days. Water activity of microparticles formed during the SD process increased during storage, whereas those formed by SC and SDC processes showed no changes in water activity. The formed microparticles exhibited color variation and size increase over time. Carotenoid degradation of the microparticles was described by zero-order kinetics for most treatments. Considering the higher carotenoid content and its stability, the optimum formulation for each process was selected to further analysis. Scanning electron micrographs revealed the spherical shape and absence of cracks on the microparticle surface, as well as size heterogeneity. SD increased the stability to oxidation of the carotenoid-rich extract by at least 52-fold, SC by threefold, and SDC by 545-fold. Analysis of the thermophysical properties suggested that the carrier and the process of encapsulation influence the powder’s thermal resistance. Water sorption data of the SDC microparticles depended on the blend of the carrier agents used in the process. Carotenoid encapsulation via an innovative combination of spray drying and spray chilling processes offers technological benefits, which could be applied as a promising alternative to protect valuable bioactive compounds.

100 Deals associated with SC-040

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Inflammation	Discovery	US	Monsanto Co.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

SC-040

Overview

Basic Info

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation