Proteolysis-targeting chimeras (PROTACs), which selectively degrade targeted proteins by the ubiquitin-proteasome system, have emerged as a novel therapeutic technology with potential advantages over traditional inhibition strategies. In the past few years, this technology has achieved substantial progress and two PROTACs have been advanced into phase I clinical trials. However, this technology is still maturing and the design of PROTACs remains a great challenge. In order to promote the rational design of PROTACs, we present PROTAC-DB, a web-based open-access database that integrates structural information and experimental data of PROTACs. Currently, PROTAC-DB consists of 1662 PROTACs, 202 warheads (small molecules that target the proteins of interest), 65 E3 ligands (small molecules capable of recruiting E3 ligases) and 806 linkers, as well as their chemical structures, biological activities, and physicochemical properties. Except the biological activities of warheads and E3 ligands, PROTAC-DB also provides the degradation capacities, binding affinities and cellular activities for PROTACs. PROTAC-DB can be queried with two general searching approaches: text-based (target name, compound name or ID) and structure-based. In addition, for the convenience of users, a filtering tool for the searching results based on the physicochemical properties of compounds is also offered. PROTAC-DB is freely accessible at http://cadd.zju.edu.cn/protacdb/.

Yes-associated protein (YAP) and its paralogue, transcriptional co-activator with PDZ-binding motif (TAZ), play pivotal roles in promoting the progression of hepatocellular carcinoma (HCC). However, the regulatory mechanism underpinning aberrant activation of YAP/TAZ in HCC remains unclear. In this study, we globally profiled the contribution of deubiquitinating enzymes (DUB) to both transcriptional activity and protein abundance of YAP/TAZ in HCC models and identified ubiquitin-specific peptidase 10 (USP10) as a potent YAP/TAZ-activating DUB. Mechanistically, USP10 directly interacted with and stabilized YAP/TAZ by reverting their proteolytic ubiquitination. Depletion of USP10 enhanced polyubiquitination of YAP/TAZ, promoted their proteasomal degradation, and ultimately arrested the proliferation of HCC in vitro and in vivo. Expression levels of USP10 positively correlated with the abundance of YAP/TAZ in HCC patient samples as well as in N-nitrosodiethylamine (DEN)-induced liver cancer mice models. Collectively, this study establishes the causal link between USP10 and hyperactivated YAP/TAZ in HCC cells and provides a rationale for potential therapeutic interventions in the treatment of HCC patients harboring a high level of YAP/TAZ. Significance: These findings identify USP10 as a DUB of YAP/TAZ and its role in HCC progression, which may serve as a potential therapeutic target for HCC treatment.

New functionally diverse urea-derived MOF hydrogen-bond-donating heterogeneous catalysts were achieved via postsynthetic modification, which exhibit excellent catalytic activity and very broad substrate scopes for the Friedel-Crafts alkylation reactions.

As the substitute of polybrominated diphenyl ethers (PBDEs), further assessments about the potential ecological safety and health risks of phosphorus-containing flame retardants (PFRs) are required because the worldwide demand for PFRs has been increasing every year. In this study, we examined the agonistic/antagonistic activity of a group of PFRs by three in vitro models (luciferase reporter gene assay, yeast two-hybrid assay, and E-screen assay). Molecule docking was used to further explain the interactions between ERα and PFRs. Data from luciferase reporter gene analysis showed three members of the nine tested PFRs significantly induced estrogenic effects, with the order of TPP > TCP > TDCPP, while TCEP and TEHP have remarkable antiestrogenic properties with calculated REC20 and RIC20 values of 10–6 M or lower. Results from the luciferase reporter gene method are generally consistent with results obtained from the yeast two-hybrid assay and E-screen, except for the positive estrogenic activity of TBP in E-screen testing. Docking results showed that binding between ligands and ERα was stabilized by hydrophobic interactions. As a proposed alternative for brominated flame retardant, PFRs may have anti/estrogenic activity via ERα at the low dose typical of residue in environmental matrix or animals. PFRs with a short chain, halogen, and benzene ring in the substituent group tend to be estrogenic. Our research suggests that comprehensive evaluations, including health and ecological assessments, are required in determining whether PFRs are preferable as an emerging industrial substitute.

Microtubules are cytoskeletal components that play important roles in a number of cellular processes. Colchicine binding site inhibitors (CSIs) is one major class of tubulin polymerization inhibitors, inhibiting microtubule polymerization and blocking cell proliferation at metaphase during mitosis. Many CSIs were discovered or designed and synthesized as anticancer agents in the past several years and great progress had been made. Here, we discuss the insights gained so far relevant to the mechanism of CSIs and their common pharmacophore. The recent development of CSIs with their biological activity and structure-activity relationship (SAR) are also reviewed.

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Background and Purpose Pyroptosis is a lytic form of pro‐inflammatory cell death characterised as caspase 1 dependent with canonical NLRP3 inflammasome‐induced gasdermin D (GSDMD) activation. We aimed to investigate the role of acinar pyroptotic cell death in pancreatic injury and systemic inflammation in AP. Experimental Approach Pancreatic acinar pyroptotic cell death pathway activation upon pancreatic toxin stimulation in vitro and in vivo was investigated. Effects of pharmacological (NLRP3 and caspase‐1 inhibitors), constitutive (Nlrp3−/−, Casp1−/− and Gsdmd−/−) and acinar cell conditional (Pdx1CreNlrp3Δ/Δ and Pdx1CreGsdmdΔ/Δ) genetic inhibition on pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation were assessed using mouse AP models (caerulein, sodium taurocholate and l‐arginine). Effects of Pdx1CreGsdmdΔ/Δ versus myeloid conditional knockout (Lyz2CreGsdmdΔ/Δ) and Gsdmd−/− versus receptor‐interacting protein 3 (RIP3) inhibitor were compared in CER‐AP. Key Results There was consistent pyroptotic acinar cell death upon pancreatic toxin stimulation both in vitro and in vivo, which was significantly reduced by pharmacological or genetic pyroptosis inhibition. Pdx1CreGsdmdΔ/Δ but not Lyz2CreGsdmdΔ/Δ mice showed significantly reduced pyroptotic acinar cell death, pancreatic necrosis and systemic inflammation in caerulein‐AP. Co‐application of RIP3 inhibitor on Gsdmd−/− mice further increased protection on caerulein‐AP. Conclusion and Implications This work demonstrates a critical role for NLRP3 inflammasome and GSDMD activation‐mediated pyroptosis in acinar cells, linking pancreatic necrosis and systemic inflammation in AP. Targeting pyroptosis signalling pathways holds promise for specific AP therapy.

Four prenylflavonoids, bavachin 1, isobavachin 2, 7,4'-dihydroxy-8-prenylflavone 3, and 8-prenylapigenin 4 were synthesized and recognized for possessing estrogen-like activity in MCF-7/BOS cells, as evaluated by an estrogen-screening assay. All compounds significantly stimulated the proliferation of MCF-7/BOS cells in a dose-dependent manner. Isobavachin 2 showed the most potent activity, while bavachin 1 was the weakest. The estrogenic potency of these compounds is ranked as follows: 2 > 4 > 3 > 1.