ABSTRACT
Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure-activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.
ABSTRACT
Objective:To investigate the effect of dexmedetomidine on cognitive function and transforming growth factor β(TGF-β)/Smad pathway in elderly patients with gastric cancer after radical operation.Methods:A total of 100 elderly patients with gastric cancer undergoing radical gastrectomy in Taizhou Central Hospital from December 2018 to December 2019 were randomly divided into observation group (50 cases) and control group (50 cases) according to the random digital table method.In the observation group, dexmedetomidine hydrochloride was given intravenously after anesthesia induction.The control group was given sodium chloride injection intravenously after anesthesia induction.The dosage of propofol and remifentanil, the time of operation, the amount of intraoperative bleeding, the occurrence of cognitive impairment (PCOD) on the 3rd and 7th day after operation, and the expression of TGF-β, Smad1 and Smad2 proteins before and after operation were compared between the two groups.Results:The dosages of propofol [(648.71±65.25)mg] and remifentanil [(0.46±0.08)mg] in the observation group were lower than those in the control group [(837.92±57.53)mg and (0.59±0.14)mg] ( t=15.380, 5.701, all P<0.05). There was no statistically significant difference between the two groups in operation time and bleeding volume (all P>0.05). The incidences of PCOD at postoperative 3d and 7d in the observation group (8.00%, 12.00%) were lower than those in the control group (26.00%, 34.00%) (χ 2=5.741, 6.832, all P<0.05). The expression of TGF-β(0.45±0.09), Smad1 (0.37±0.06) and Smad2 (0.36±0.04) in the observation group were lower than those in the control group [(0.60±0.18), (0.47±0.08) and (0.42±0.11)] ( t=5.271, 7.071, 3.625, all P<0.05). Conclusion:Dexmedetomidine can reduce PCOD and downregulate the protein expression of TGF-β/Smad pathway.
ABSTRACT
Adenine derivatives, in particular the scaffold bearing the acyclic nucleoside phosphonates (ANPS), possess significant antiviral and cytostatic activity. Till now, several effective adenine derivatives have been marketed for the treatment of HIV, HBV, CMV and other virus-infected diseases. These compounds are represented by tenofovir (PMPA), a medicine for both HIV and HBV, and adefovir as an anti-HBV agent. More than this, other analogs, such as GS9148, GS9131, and GS7340, are also well-known anti-viral agents that have been progressed to the clinical studies for their excellent activity. In general, the structures of these compounds include an adenine nucleobase linked to a phosphonate side chain. Considerable structural modifications on the scaffold itself and the peripheral sections were made. The structure-activity relationships (SARs) of this skeleton will provide valuable clues to identify more effective adenine derivatives as antiviral drugs. Here, we systematically summarized the SARs of the adenine derivatives, and gave important information for further optimizing this template.