Degradation of proteins by PROTACs and other strategies

Blocking the biological functions of scaffold proteins and aggregated proteins is a challenging goal. PROTAC proteolysis-targeting chimaera (PROTAC) technology may be the solution, considering its ability to selectively degrade target proteins. Recent progress in the PROTAC strategy include identification of the structure of the first ternary eutectic complex, extra-terminal domain-4-PROTAC-Von-Hippel-Lindau (BRD4-PROTAC-VHL), and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019. These discoveries strongly proved the value of the PROTAC strategy. In this perspective, we summarized recent meaningful research of PROTAC, including the types of degradation proteins, preliminary biological data in vitro and in vivo, and new E3 ubiquitin ligases. Importantly, the molecular design, optimization strategy and clinical application of candidate molecules are highlighted in detail. Future perspectives for development of advanced PROTAC in medical fields have also been discussed systematically.

Advances of covalently modified drugs / 中国药科大学学报

Covalently modified drugs,which exert their pharmacological effects by covalently binding to the targets,have been avoided as far as possible for a long time in drug design due to the potential off-target effects and other side-effects.With the in-depth study of binding modes of market blockbuster covalent drugs,more and more attention has been concentrated on covalently modified drugs.Current challenges remain in development of potent selective covalently modified drugs with fewer adverse effects.This paper reviews the classification of some covalently modified drugs,the drug-target binding modes and the new strategies of designing covalently modified drugs,in order to provide reference for rational design of covalent drugs.

Advances in small-molecule inhibitors targeting Hsp90-Cdc37 protein-protein interaction / 中国药科大学学报

@#Heat shock protein 90(Hsp90)which is a molecular chaperone that integrates multiple oncogenic pathways, is an important target in cancer therapy. The present research and development of the traditional N-terminal and C-terminal inhibitors has been restricted while targeting Hsp90 and cell division cycle protein Cdc37 has become the new direction of inhibiting Hsp90. Previous studies have demonstrated that various protein kinases rely on Cdc37 to load onto Hsp90 to complete their correct folding. Thus targeting Hsp90-Cdc37 is a promising strategy to inhibit protein kinases and alleviate the side effects. The interaction mechanism between Hsp90 and Cdc37 has become clearer in recent studies and many natural products have been reported to possess the ability to disassociate Hsp90-Cdc37. In this review, current knowledge on these small molecule inhibitors are summarized. The mode of action is also discussed as the references for the development of novel Hsp90 inhibitors.

Progress in research of the structural optimization of natural product-like Garcinia caged xanthones / 药学学报

Designing of natural product-like compounds using natural products as template structures is an important strategy for the discovery of new drugs. Gambogic acid (GA), which is a Garcinia natural product with a unique caged xanthone scaffold, inhibits potent antitumor activity both in vitro and in vivo. This review summarized the researches on the identification of the antitumor pharmacophore of GA, and the design, structural optimization and structure-activity relationship (SAR) of natural product-like caged xanthones based on it.

Time-relative-intensity curve of contrast-enhanced ultrasonography for discrimination of malignant and benign liver tumors / 中华超声影像学杂志

Objective To study the diagnostic value of relative parameters and time-relative-intensity curve(TRIC) in malignant and benign liver tumors with contrast-enhanced ultrasound(CEUS). Methods Fifty-nine focal liver lesions were examined with CEUS and drawed time-intensity curve(TIC) with QLAB software. The relative parameters of malignant and benign liver tumors were calculated and analysed. The relative intensity equaled the echo intensity of lesion substracted the encho intensity of liver. TRIC were drawed with time as abscissa and relative intensity as the ordinate. The types of TIRC were analysed comparatively in different groups (benign and malignant). Results There were significant differences in relative peak time, relative peak intensity, relative enhancement time and relative decline slope between malignant and benign lesions( P ＜0. 05). TRIC appeared quick-ascending and quick-descending types in the malignant lesions,the decline curve of TRIC droped down to 0 dB at (28.24 ± 8. 14)s and down to lowest - 8 dB continually, meanwhile fluctuated slightly. While TRIC appeared slow-ascending and slow-descending types in the benign lesions, the decline curve of TRIC droped down to the lowest 4 dB continually, meanwhile fluctuated slightly. Conclusions The relative parameters and TRIC are new quantitative indicators of CEUS for diagnosis of malignant and benign liver tumors.