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There is a lack of effective treatments to overcome resistance to EGFR-TKIs in EGFR mutant tumors. A deeper understanding of resistance mechanisms can provide insights into reducing or eliminating resistance, and can potentially deliver targeted treatment measures to overcome resistance. Here, we identified that the dynamic changes of the tumor immune environment were important extrinsic factors driving tumor resistance to EGFR-TKIs in EGFR mutant cell lines and syngeneic tumor-bearing mice. Our results demonstrate that the acquired resistance to EGFR-TKIs is accompanied by aberrant expression of PD-L2, leading a dynamic shift from an initially favorable tumor immune environment to an immunosuppressive phenotype. PD-L2 expression significantly affected EGFR mutant cell apoptosis that depended on the proportion and function of CD8+T cells in the tumor immune environment. Combined with single-cell sequencing and experimental results, we demonstrated that PD-L2 specifically inhibited the proliferation of CD8+T cells and the secretion of granzyme B and perforin, leading to reduced apoptosis mediated by CD8+T cells and enhanced immune escape of tumor cells, which drives EGFR-TKIs resistance. Importantly, we have identified a potent natural small-molecule inhibitor of PD-L2, zinc undecylenate. In vitro, it selectively and potently blocks the PD-L2/PD-1 interaction. In vivo, it abolishes the suppressive effect of the PD-L2-overexpressing tumor immune microenvironment by blocking PD-L2/PD-1 signaling. Moreover, the combination of zinc undecylenate and EGFR-TKIs can synergistically reverse tumor resistance, which is dependent on CD8+T cells mediating apoptosis. Our study uncovers the PD-L2/PD-1 signaling pathway as a driving factor to mediate EGFR-TKIs resistance, and identifies a new naturally-derived agent to reverse EGFR-TKIs resistance.

Gout is characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals around joints. Despite the availability of several drugs on the market, its treatment remains challenging owing to the notable side effects, such as hepatorenal toxicity and cardiovascular complications, that are associated with most existing agents. This perspective aims to summarize the current research progress in the development of antigout agents, particularly focusing on xanthine oxidase (XO) and urate anion transporter 1 (URAT1) inhibitors from a medicinal chemistry viewpoint and their preliminary structure–activity relationships (SARs). This perspective provides valuable insights and theoretical guidance to medicinal chemists for the discovery of antigout agents with novel chemical structures, better efficiency, and lower toxicity.

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 N11was the most promising inhibitor, showing an IC50value of 6.3 nM against the PD-1/PD-L1 interaction at the biochemical level. In in vitroT-cell tumor co-culture models, N11significantly promoted T-cell proliferation, activation, and infiltration into tumor spheres, demonstrating that it possessed excellent immunomodulatory activity. In addition, N11exhibited 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 N11was dependent on the activation of the immune microenvironment. These findings suggest that N11can serve as a new starting point for the future development of small-molecule antitumor immunomodulators targeting the PD-1/PD-L1 axis.

Plinabulin is a selective small-molecule tumor vascular-disrupting agent that may also be used to treat chemotherapy-induced neutropenia. However, the original synthetic procedure of plinabulin exhibits several limitations. The raw material, ethyl isocyanoacetate, is expensive, with an unpleasant odor that may harm workers. The intermediates generally require purification using column chromatography, which is not a preferred purification method on a large scale. In addition, the extended synthetic route does not satisfy the requirements of green chemistry. Therefore, a novel, improved method of synthesizing plinabulin is reported based on the syntheses and isolation of the key intermediate 8, 4-(tert-butyl)-1H-imidazole-5-carbaldehyde, and the final product. The advantages of this method include simple post-treatment, less residual solvent, nontoxicity, and convenient execution. Furthermore, the final product is obtained via a one-pot method, which satisfies the requirements of green chemistry and is thus suitable for use in industrial production.

Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30exhibited outstanding biochemical activity, with an IC50of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30showed favorable in vivoantitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30inhibited tumor growth by activating the immune microenvironment. We concluded that A30is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.

Triboelectric tactile sensing technique is increasingly coming into people’s lives to bring convenience, so that there is an urgent necessity for this technique to be applied to smart mobility to increase safety and enhance the mobility experience. Herein, a single-electrode mode multilayer triboelectric sensor (MTS) motivated by artificial intelligence (AI) is proposed, which consists of styrene-butadiene-styrene (SBS)/ poly (vinylida-ene fluoride-trifluoroethylene) (PVDF-TrFE) nanofibers (NFs) film as the friction layer and substrate, laser-induced graphene (LIG)/molybdenum disulfide (MoS2) as the charge trapping layer, and Ag as the electrode. The MTS exhibits remarkable sensing performance, such as a wide response range of 5-100N, 0.4-2Hz multi-frequency response capability, and non-contact sensing, as well as distinguished self-powered performance. To demonstrate the practical significance of the proposed MTS, two applications are explored specifically after equipping with AI, including: (i) a smart in-vehicle system is constructed, which consists of unlocking section and multifunctional control with early warning section. (ii) a smart car control system is implemented, which can carry out special tasks instead of humans. These applications provide reliable ways to promote the development of human-machine interaction and smart mobility, as well as help to make lifestyles and mobility smarter, safer and more convenient.

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction using small-molecule inhibitors is an emerging immunotherapeutic approach. A novel series of [1,2,4]triazolo[4,3-a]pyridines were designed and found to be potent inhibitors of the PD-1/PD-L1 interaction. Among them, compound A22exhibited the most potent activity, as assessed by homogenous time-resolved fluorescence assay, with an IC50of 92.3 nM. Furthermore, A22dose-dependent elevated interferon-γ production in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. We concluded that A22is a promising lead compound for the development of inhibitors of the PD-1/PD-L1 interaction. In addition, we explored the structure–activity relationships of the newly synthesized [1,2,4]triazolo[4,3-a]pyridines and demonstrated that a ring fusion strategy can be employed for designing analogues of the Bristol-Myers Squibb chemical series. These studies pave the way for future drug design.

A novel series of diaryl biuret derivatives containing a tetrazole moiety was designed and synthesized. All the target compounds were evaluated for their in vitroantitumor activity against HT-29, HepG2, MCF-7 and A549 cells by MTT assay. Most of them exhibited obvious antitumor activity, and four of them(4a, 4c, 4h and 7a) were superior to sorafenib in general. Among them, Compound 4h displayed more potent activity than sorafenib in all tested cancer cells. Compound 4c exhibited the most outstanding activity in inhibition of growth of HepG2 cells(IC50=0.55 μmol/L). Further, they both revealed favorable metabolic stability in in vitroassay. Compounds 4c and 4h are promising candidates for further development.