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Programmed cell death protein 1/programmed cell death 1 ligand 1(PD-1/PD-L1) protein-protein interaction represents an appealing target for cancer therapy. Several antibody drugs have been developed to target this interaction, but they are less effective in the treatment of melanoma. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules simultaneously targeting PD-L1 and Src homology phosphotyrosyl phosphatase 2 (SHP2) were designed. By employment of PD-1/PD-L1 inhibitors BMS01 or BMS-37, SHP2 inhibitor SHP099 and E3 ligase ligands, a series of potent PD-L1 and SHP2 dual PROTACs were synthesized. The most promising compounds BS-7C-V2and BS327V2efficiently induced PD-L1 and SHP2 degradation and demonstrated significantly improved immune potency in B16-F10 and A375 cell lines. More importantly, the efficacy of BS-7C-V2and BS327V2in a B16-F10 transplanted mouse model was further evaluated based on their degradation ability in vivo. Taken together, our work qualifies the new dual PROTACs as a potent degrader of PD-L1 and SHP2. The biological and mechanism investigations with BS-7C-V2and BS327V2prove that dual PROTACs can play an anti-tumor role in vivo and in vitro, and can provide a new therapeutic strategy for melanoma.

Lead-halide perovskites exhibit outstanding performance in X-ray detection due to their intrinsic features such as high charge carrier mobility, large atomic number, and long carrier lifetime, but the toxicity of lead is regarded as the major factor hindering their development. Here, we introduce organic molecule (R)-(-)-2-methylpiperazine (R-MPz) into the bismuth-based structure to synthesize lead-free (R)-(H2MPz)BiI5(R-MBI). The high-quality centimeter-sized single crystals have been obtained, which show a low dark current and superior environmental stability. Particularly, the single-crystal device of R-MBI exhibits a high μτproduct up to 1.88 × 10−4cm2/V and a low trap density of 1.21 × 1010cm−3. Further, the detector displays excellent detection sensitivity of 263.58 μC Gyair−1cm−2and a favorable low detection limit of 4.35 μGyair/s, both of which meet the requirement for medical diagnostics. These findings shed light on the exploration of innovative bismuth-based hybrid perovskites for high-performance X-ray detection.

Two new homoisoflavanones were isolated from the rhizomes of Polygonatum odoratum(Mill.) Druce and their structures were elucidated as (3R)-5,7-dihydroxy-8-methoxy-3-(4-methoxybenzyl)-6-methylchrom-an-4-one (1) and (3R)-5,7,8-trihydroxy-3-(4-hydroxybenzyl)-6-methylchroman-4-one (2), on the basis of sp-ectral analysis.

Two new isomeric compounds of rare acyclic C13-norisoprenoids, along with two known lignans sauchinone and licarin A, were isolated from the herb of Saururus chinensis (Lour.) Baill. Their structures were elucidated on the basis of spectral analysis.