Targeting EGFR degradation by autophagosome degraders.

Several generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed for the treatment of non-small cell lung cancer (NSCLC) in clinic. However, emerging drug resistance mediated by new EGFR mutations or activations by pass, leads to malignant progression of NSCLC. Proteolysis targeting chimeras (PROTACs) have been utilized to overcome the drug resistance acquired by mutant EGFR, newly potent and selective degraders are still need to be developed for clinical applications. Herein, we developed autophagosome-tethering compounds (ATTECs) in which EGFR can be anchored to microtubule-associated protein-1 light chain-3B (LC3B) on the autophagosome with the assistance of the LC3 ligand GW5074. A series of EGFR-ATTECs have been designed and synthesized. Biological evaluations showed that these compounds could degrade EGFR and exhibited moderate inhibitory effects on certain NSCLC cell lines. The ATTEC 12c potently induced the degradation of EGFR with a DC50 value of 0.98 µM and a Dmax value of 81% in HCC827 cells. Mechanistic exploration revealed that the lysosomal pathway was mainly involved in this degradation. Compound 12c also exhibited promising inhibitory activity, as well as degradation efficiency in vivo. Our study highlights that EGFR-ATTECs could be developed as a new expandable EGFR degradation tool and also reveals a novel potential therapeutic strategy to prevent drug resistance acquired EGFR mutations.

Discovery of Novel Polycyclic Phloroglucinols via an Improved One-Pot Method.

In nature, polycyclic phloroglucinols are a class of compounds with considerable structural diversity and promising biological activities. Herein, we present an improved one-pot method that replaces the solution reaction conditions by mixing the reactants with column chromatography silica gel. Through this convenient, mild, slow, and diversity-oriented strategy, eight structurally unique polycyclic phloroglucinols were discovered, of which compound 1 possesses a rare cage-like skeleton. All compounds determined their structures by X-ray diffraction. Compared with traditional methods, this synthetic strategy produced better diversity and unique structures under milder conditions, suggesting that this method has great potential in lead compound discovery. The optimal reaction conditions were determined by high-performance liquid chromatography (HPLC) monitoring over time. In addition, density functional theory (DFT) calculations were performed to investigate the possible generative pathway of compound 1. We also examined the neuroprotective actions of selected compounds on SH-SY5Y cells and the MPP+-induced Caenorhabditis elegans PD model.

Nesting Co3Mo Binary Alloy Nanoparticles onto Molybdenum Oxide Nanosheet Arrays for Superior Hydrogen Evolution Reaction.

Transition-metal alloys have attracted a great deal of attention as an alternative to Pt-based catalysts for hydrogen evolution reaction (HER) in alkaline. Herein, a facile and convenient strategy to fabricate Co3Mo binary alloy nanoparticles nesting onto molybdenum oxide nanosheet arrays on nickel foam is developed. By modulating the annealing time and temperature, the Co3Mo alloy catalyst displays a superior HER performance. Owing to substantial active sites of nanoparticles on nanosheets as well as the intrinsic HER activity of Co3Mo alloy and no use of binders, the obtained catalyst requires an extremely low overpotential of only 68 mV at 10 mA cm-2 in alkaline, with a corresponding Tafel slope of 61 mV dec-1. At the same time, the catalyst demonstrates excellent stability during the long-term measurements. The density functional theory calculation provides a deeper insight into the HER mechanism, unveiling that the active sites on the Co3Mo-based catalyst are Mo atoms. This strategy of combining catalytic active species with hierarchical nanoscale materials can be extended to other applications and provides a candidate of nonnoble metal catalysts for practical electrochemical water splitting.

Pd-Co nanoalloys nested on CuO nanosheets for efficient electrocatalytic N2 reduction and room-temperature Suzuki-Miyaura coupling reaction.

Due to their synergistic and tunable effects, bimetallic alloy systems have recently attracted considerable attention as superior catalysts. Herein, Pd-Co bimetallic alloy nanoparticles were uniformly deposited onto CuO nanosheet supports. This nanostructured catalyst was first shown to be an effective catalyst to convert N2 to NH3 in 0.1 M KOH with a yield of 10.04 µg h-1 mg-1cat. and a faradaic efficiency of 2.16%. The catalyst also performed well in the Suzuki-Miyaura coupling reaction at room temperature without an inert atmosphere and any toxic solvents. Thus, the catalyst is consistent with the principles of green chemistry. Due to the synergistic effects, this bimetallic Pd-Co catalyst shows higher catalytic activity than its monometallic counterparts. Moreover, the Pd/Co ratio was tuned to achieve the best catalytic performance. Finally, the Pd-Co/CuO catalyst presented good stability and recyclability. The superior catalytic activity of the bimetallic alloy catalyst make it an alternative material for catalytic applications in the future.