Search

Two series of proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were identified. Compound A16 displayed the most potent inhibition against LNCaP and showed excellent AR degradation efficacy at 30 μM. [Display omitted] • Two series of novel PROTACs and androgen receptor degradation efficacy have been discovered. • The best compound A16 displayed excellent binding affinity and AR degradation activity. • Molecular docking analysis illustrates the possible dual mechanism actions of these compounds with AR and E3 ligase. As a continuation of our research on developing potent and potentially safe androgen receptor (AR) degrader, a series of novel proteolysis targeting chimeras (PROTACs) containing the phthalimide degrons with different linker were designed, synthesized and evaluated for their AR degradation activity against LNCaP (AR+) cell line. Most of the synthesized compounds displayed moderate to satisfactory AR binding affinity and might lead to antagonist activity against AR. Among them, compound A16 exhibited the best AR binding affinity (85%) and degradation activity against AR. Due to the strong fluorescence properties of pomalidomide derivatives, B10 was found to be effectively internalized and visualized in LNCaP (AR +) cells than PC-3 (AR-) cells. Moreover, the molecular docking of A16 with AR and the active site of DDB1-CRBN E3 ubiquitin ligase complex provides guidance to design new PROTAC degrons targeting AR for prostate cancer therapy. These results represent a step toward the development of novel and improved AR PROTACs. [ABSTRACT FROM AUTHOR]

Objective: To obtain high?quality low?dose CT images using total generalized variation regularization based on the projection data for low?dose CT reconstruction., Methods: The projection data of the CT images were transformed from Poisson distribution to Gaussian distribution using the linear Anscombe transform. The transformed data were then restored by an efficient total generalized variation minimization algorithm. Reconstruction was finally achieved by inverse Anscombe transform and filtered back projection (FBP) method., Results: The image quality of low?dose CT was greatly improved by the proposed algorithm in both Clock and Shepp?Logan phantoms. The signal?to?noise ratios (SNRs) of the Clock and Shepp-Logan images reconstructed by FBP algorithm were 17.752 dB and 19.379 dB, which were increased by the proposed algorithm to 24.0352 and 23.4181 dB, respectively. The NMSE of the Clock and Shepp?Logan images reconstructed by FBP algorithm was 0.86% and 0.58%, which was reduced by the proposed algorithm to 0.2% and 0.23%, respectively., Conclusion: The proposed method can effectively suppress noise and strip artifacts in low?dose CT images when piecewise constant assumption is not possible.