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Targeted Protein Degradation (TPD) represented by Proteolysis-Targeting Chimeras (PROTAC) is the frontier field in the research and development of antitumor therapy, in which oral drug HP518 Receives FDA Proceed Authorization for its IND Application for Prostate Cancer Treatment. Recently, molecular glue, functioning via degradation of the target protein is emerging as a promising modality for the development of therapeutic agents, while exhibits greater advantages over PROTAC, including improved efficiency, resistance-free properties, and the capacity to selectively target “undruggable” proteins. This marks a revolutionary advancement in the landscape of small molecule drugs. Given that molecular glue research is still in its early stage, we summarized the mechanisms of molecular glue, the promising drugs in clinical trials and diverse feasible design strategies for molecular glue therapeutics.

BackgroundColorectal cancer (CRC) is the 3rd most common cancer in men and 2nd most common malignancy in females across the globe leading to high mortality rates. Frailty is an age-related syndrome that has been associated with high morbidity and mortality. This systematic review aimed to examine if frailty can predict long-term (>1 year) outcomes of patients with CRC.MethodsThis PROSPERO registered review examined the databases of PubMed, Embase, and Web of Science till 4th September 2023 for cohort studies assessing the association between frailty and long-term outcomes of CRC.Results15 studies with 45288 patients were included. 6573 patients (14.5%) were frail. Meta-analysis demonstrated that frailty was associated with statistically significant poor overall survival (OS) (HR: 2.11 95% CI: 1.44, 3.08 I2 = 94%) (14 studies), cancer-specific survival (CSS) (HR: 4.59 95% CI: 2.75, 7.67 I2 = 38%) (2 studies), and disease-free survival (DFS) (HR: 1.46 95% CI: 1.28, 1.66 I2 = 0%) (5 studies) after CRC. Subgroup analysis for OS based on study type, location, sample size, stage of cancer, percentage with frailty, treatment, adjustment for CRC stage and comorbidities, and follow-up did not change the results. These results were not altered in significance on sensitivity analysis.ConclusionOur results show that frail CRC patients have poor OS and DFS as compared to non-frail patients. Variations in frailty measurement tools and high inter-study heterogeneity are major limitations of the review.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, PROSPERO, CRD42023450586

IntroductionWith the increasingly serious problem of bacterial drug resistance caused by NDM-1, it is an important strategy to find effective inhibitors to assist β-lactam antibiotic treatment against NDM-1 resistant bacteria. In this study, PHT427 (4-dodecyl-N-1,3,4-thiadiazol-2-yl-benzenesulfonamide) was identified as a novel NDM-1 inhibitor and restored the susceptibility of meropenem against Enterobacteriaceae producing NDM-1.MethodsWe used a high throughput screening model to find NDM-1 inhibitor in the library of small molecular compounds. The interaction between the hit compound PHT427 and NDM-1 was analyzed by fluorescence quenching, surface plasmon resonance (SPR) assay, and molecular docking analysis. The efficacy of the compound in combination with meropenem was evaluated by determining the FICIs of Escherichia coli BL21(DE3)/pET30a(+)-blaNDM–1 and Klebsiella pneumoniae clinical strain C1928 (producing NDM-1). In addition, the mechanism of the inhibitory effect of PHT427 on NDM-1 was studied by site mutation, SPR, and zinc supplementation assays.ResultsPHT427 was identified as an inhibitor of NDM-1. It could significantly inhibit the activity of NDM-1 with an IC50 of 1.42 μmol/L, and restored the susceptibility of meropenem against E. coli BL21(DE3)/pET30a(+)-blaNDM–1 and K. pneumoniae clinical strain C1928 (producing NDM-1) in vitro. The mechanism study indicated that PHT427 could act on the zinc ions at the active site of NDM-1 and the catalytic key amino acid residues simultaneously. The mutation of Asn220 and Gln123 abolished the affinity of NDM-1 by PHT427 via SPR assay.DiscussionThis is the first report that PHT427 is a promising lead compound against carbapenem-resistant bacteria and it merits chemical optimization for drug development.

Liver X receptors (LXRs) are important regulators of cholesterol metabolism and inflammatory responses. LXR agonists exhibit potently anti-inflammatory effects in macrophages, which make them beneficial to anti-atherogenic therapy. In addition to transrepressive regulation by SUMOylation, LXRs can inhibit inflammation by various mechanisms through affecting multiple targets. In this study, we found that the classic LXR agonist T0901317 mediated numerous genes containing alternative splice sites, including myeloid differentiation factor 88 (MyD88), that contribute to inflammatory inhibition in RAW264.7 macrophages. Furthermore, T0901317 increased level of alternative splice short form of MyD88 mRNA by down-regulating expression of splicing factor SF3A1, leading to nuclear factor κB-mediated inhibition of inflammation. In conclusion, our results suggest for the first time that the LXR agonist T0901317 inhibits lipopolysaccharide-induced inflammation through regulating MyD88 mRNA alternative splicing involved in TLR4 signaling pathway.

Phenethyl isothiocyanate is widely present in cruciferous vegetables with multiple biological effects. Here we reported the antiatherogenic effects and the underlying mechanisms of JC-5411 (Phenethyl isothiocyanate formulation) in vitro and in vivo. Luciferase reporter assay showed that JC-5411 increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE). JC-5411 treatment significantly increased the protein expression of Nrf2 and its downstream target gene hemeoxygenase 1 (HO-1) in liver of apolipoprotein E deficient (ApoE−/−) mice. Importantly, JC-5411 treatment significantly reduced atherosclerotic plaque area in both en face aorta and aortic sinus when compared with model group in WD induced ApoE−/− mice. JC-5411 obviously decreased proinflammatory factors’ levels in serum of ApoE−/− mice, LPS stimulated macrophages and TNFα induced endothelial cells, respectively. JC-5411 significantly decreased the levels of total cholesterol (TC) and triglyceride (TG) in both serum and liver of ApoE−/− mice and hyperlipidemic golden hamsters. Mechanism studies showed that JC-5411 exerted anti-inflammatory effect through activating Nrf2 signaling and inhibiting NF-κB and NLRP3 inflammasome pathway. JC-5411 exerted regulating lipid metabolism effect through increasing cholesterol transfer proteins (ABCA1 and LDLR) expression, regulating fatty acids synthesis related genes (p-ACC, SCD1 and FAS), and increasing fatty acids β-oxidation (CPT1A) in vivo. Furthermore, JC-5411 treatment had a favorable antioxidant effect in ApoE−/− mice by increasing the antioxidant related genes expression. Taken together, we conclude that JC-5411 as a Nrf2 activator has anti-inflammatory, rebalancing lipid metabolism, and antioxidant effects, which makes it as a potential therapeutic agent against atherosclerosis.