Modular Development of Enzyme-Activatable Proteolysis Targeting Chimeras for Selective Protein Degradation and Cancer Targeting.

As an emerging therapeutic modality, proteolysis targeting chimeras (PROTACs) indiscriminately degrade proteins in both healthy and diseased cells, posing a risk of on-target off-site toxicity in normal tissues. Herein, we present the modular development of enzyme-activatable PROTACs, which utilize enzyme-recognition moieties to block protein degradation activities and can be specifically activated by elevated enzymes in cancer cells to enable cell-selective protein degradation and cancer targeting. We identified the methylene alkoxy carbamate (MAC) unit as an optimal self-immolative linker, possessing high stability and release efficiency for conjugating enzyme-recognition moieties with PROTACs.

Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 inhibitors: Research progress and prospects.

The cancer immunotherapies involved in cGAS-STING pathway have been made great progress in recent years. STING agonists exhibit broad-spectrum anti-tumor effects with strong immune response. As a negative regulator of the cGAS-STING pathway, ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can hydrolyze extracellular 2', 3'-cGAMP and reduce extracellular 2', 3'-cGAMP concentration.

Discovery of 1,3,4-oxadiazole derivatives as potential antitumor agents inhibiting the programmed cell death-1/programmed cell death-ligand 1 interaction.

Inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by small-molecule inhibitors is emerging cancer immunotherapy. A series of novel 1,3,4-oxadiazole derivatives were designed, synthesized, and evaluated for their activities in vitro and vivo to find potent inhibitors of the PD-1/PD-L1 interaction. Among them, compoundⅡ-14exhibited outstanding biochemical activity, with an ICof 0.

Discovery of 3,5-dimethylisoxazole derivatives as novel, potent inhibitors for bromodomain and extraterminal domain (BET) family.

Bromodomain and extra-terminal (BET) is a promising therapeutic target for various hematologic cancers. We used the BRD4 inhibitor compound 13 as a lead compound to develop a variety of compounds, and we introduced diverse groups into the position of the compound 13 orienting toward the ZA channel. A series of compounds (14-23, 38-41, 43, 47-49) bearing triazolopyridazine motif exhibited remarkable BRD4 protein inhibitory activities.

Insight into the dichotomous regulation of STING activation in immunotherapy.

Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway (cGAS-STING) is a hub linking innate immunity and adaptive immunity against pathogen infection by inducing the production of type I interferon (IFN-I). It also plays pivotal roles in modulating tumorigenesis by ensuring the antigen presentation, T cell priming, activation, and tumor regression. Given its antitumor immune properties, cGAS-STING has attracted intense focus and several STING agonists have entered into clinical trials.

Identification of 3,5-Dimethylisoxazole Derivatives as BRD4 Inhibitors for the Treatment of Colorectal Cancer.

Bromodomain-containing protein 4 (Brd4) plays a critical regulatory role in gene transcription that has been recently recognized as a promising strategy for cancer therapy. Based on the BRD4 protein containing two tandem bromodomain structures, BD1 and BD2, we designed and synthesized a series of 3,5-dimethylisoxazole derivative dimers targeting both bromodomains simultaneously to enhance protein binding potency. Among them, compound significantly inhibited the proliferation of colorectal cancer cells HCT116 (IC = 162 nM), with a 20-fold increase in antiproliferative activity compared to inhibitor .