Discovery of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety as potent inhibitors of the PD-1/PD-L1 interaction.

With the great success of anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies in clinical applications, blocking the PD-1/PD-L1 pathway has become the most compelling strategy in the field of tumor immunotherapy. In this study, a novel series of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety were developed, and their structure-activity relationships were preliminarily discussed. Among them, compounds M17 and M23 exhibited the most potent ability to disrupt the PD-1/PD-L1 interaction, demonstrating IC50 values of 60.1 nM and 53.2 nM, respectively. The binding mode of M23 was further explored by molecular docking analysis with dimeric PD-L1. Therefore, M17 and M23 are promising lead compounds for developing potent inhibitors of the PD-1/PD-L1 axis.

Novel 4-Arylindolines Containing a Pyrido[3,2-d]pyrimidine Moiety as the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction Inhibitors for Tumor Immunotherapy.

A series of pyrido[3,2-d]pyrimidine-containing 4-arylindolines were identified as potent inhibitors of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by structural optimization of a 4-arylindoline precursor reported previously. Among them, compound N11 was the most promising inhibitor, showing an IC50 value of 6.3 nM against the PD-1/PD-L1 interaction at the biochemical level. In in vitro T-cell tumor co-culture models, N11 significantly promoted T-cell proliferation, activation, and infiltration into tumor spheres, demonstrating that it possessed excellent immunomodulatory activity. In addition, N11 exhibited favorable in vivo antitumor activity in an LLC/PD-L1 tumor-bearing mouse model. Flow cytometry analysis verified that the in vivo antitumor efficacy of N11 was dependent on the activation of the immune microenvironment. These findings suggest that N11 can serve as a new starting point for the future development of small-molecule antitumor immunomodulators targeting the PD-1/PD-L1 axis.

Different regulatory processes control pollen hydration and germination in Arabidopsis.

To elucidate the functional differences in how Arabidopsis stigmas regulate pollen hydration and germination, we analyzed receptivity of stigmas, epidermal surfaces (leaves, stems of inflorescence bolts, and floral organs), and an abiotic surface (cover glass) for pollen hydration and germination. Using 65% relative humidity (RH), we found that mature pollen grains were able to hydrate and germinate on stigmas at flower developmental stages 9-13, but not on the distal end of pistils at stage 8, epidermal surfaces, or glass. Furthermore, under 100% RH, pollen grains could hydrate on all tested surfaces, but pollen germination was observed only on the young floral organs (stages 9-12) and the stigmas at stages 9-13. The distal ends of pistils at stage 8, the epidermal surfaces, and the cover glass did not support pollen germination even under 100% RH. Our results indicate that pistil factors regulating pollen hydration and germination are synthesized at stage 9 when stigmatic papillar cells begin to develop. Although pistil factors involved in pollen hydration may only be present on the stigma, the factors involved in pollen germination may localize on both the stigma and surfaces of unopened floral organs.

Tubular actin filaments in tobacco guard cells.

The dynamic remodeling of actin filaments in guard cells functions in stomatal movement regulation. In our previous study, we found that the stochastic dynamics of guard cell actin filaments play a role in chloroplast movement during stomatal movement. In our present study, we further find that tubular actin filaments are present in tobacco guard cells that express GFP-mouse talin; approximately 2.3 tubular structures per cell with a diameter and height in the range of 1-3 µm and 3-5 µm, respectively. Most of the tubular structures were found to be localized in the cytoplasm near the inner walls of the guard cells. Moreover, the tubular actin filaments altered their localization slowly in the guard cells of static stoma, but showed obvious remodeling, such as breakdown and re-formation, in moving guard cells. Tubular actin filaments were further found to be colocalized with the chloroplasts in guard cells, but their roles in stomatal movement regulation requires further investigation.