Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved. Herein, we developed a compound library based on a novel electrophilic warhead, the sulfonyl ynamide, and executed phenotypic screening against pancreatic cancer cell lines. Notably, one compound A16 exhibiting potent cell toxicity was identified. Further chemical proteomics investigations have demonstrated that A16 specifically targets GPX4 under both in situ and in vivo conditions, inducing ferroptosis. Importantly, A16 exhibited superior selectivity and potency compared to reported GPX4 inhibitors, ML210 and ML162. This provides the structural diversity of tool probes for unraveling the fundamental biology of GPX4 and exploring the therapeutic potential of pancreatic cancer via ferroptosis induction.

Simultaneous Covalent Modification of K-Ras(G12D) and K-Ras(G12C) with Tunable Oxirane Electrophiles.

Owing to their remarkable pharmaceutical properties compared to those of noncovalent inhibitors, the development of targeted covalent inhibitors (TCIs) has emerged as a powerful method for cancer treatment. The K-Ras mutant, which is prevalent in multiple cancers, has been confirmed to be a crucial drug target in the treatment of various malignancies. However, although the K-Ras(G12D) mutation is present in up to 33% of K-Ras mutations, no covalent inhibitors targeting K-Ras(G12D) have been developed to date. The relatively weak nucleophilicity of the acquired aspartic acid (12D) residue in K-Ras may be the reason for this. Herein, we present the first compound capable of covalently engaging both K-Ras(G12D) and K-Ras(G12C) mutants. Proteome profiling revealed that this compound effectively conjugates with G12C and G12D residues, modulating the protein functions in situ. These findings offer a unique pathway for the development of novel dual covalent inhibitors.

Discovery of Hexahydrofuro[3,2-b]furans as New Kinase-Selective and Orally Bioavailable JAK3 Inhibitors for the Treatment of Leukemia Harboring a JAK3 Activating Mutant.

Janus kinase 3 (JAK3) is a potential target for the treatment of hematological malignancies. Herein, we report the discovery of a series of new orally bioavailable irreversible JAK3 kinase inhibitors. The representative compound 12n potently inhibited JAK3 kinase activity with an IC50 value of 1.2 nM and was more than 900-fold selective over JAK1, JAK2, and Tyk2. Cell-based assays revealed that 12n significantly suppressed phosphorylation of JAK3 and the downstream effectors STAT3/5 and also robustly restrained proliferation of BaF3 cells transfected with JAK3M511I activating mutation and human leukemia U937 cells harboring JAK3M511I with IC50 values of 22.9 and 20.2 nM, respectively. More importantly, 12n showed reasonable pharmacokinetic (PK) properties, and oral administration of 12n at a dose of 50 mg/kg twice daily led to tumor regression in a U937 cell inoculated xenograft mouse model. Thus, 12n represents a promising lead compound for further optimization to discover new therapeutic agents for hematological malignancies.

Effect of the Nickel Source on the Structure, Performance, and Carbon Deposition of the Ni/Al2O3 Catalyst for CO2-CH4 Reforming.

Ni/Al2O3 catalysts were prepared with Ni(NO3)2·6H2O, NiSO4·6H2O, NiCl2·6H2O, and NiC4H6O4·4H2O as nickel sources by the solution combustion method. The catalysts were characterized by X-ray diffraction, H2 temperature-programmed hydrogenation, TG-DTG, TPH, and transmission electron microscopy methods, and the effect of the nickel source on performance of the Ni/Al2O3 catalyst was investigated via the CO2-CH4 reforming experiment. Results showed that Ni dispersion, Ni size, and the metal-support interaction between active component Ni and the support were influenced significantly by anion in nickel sources, resulting in that the performance of each catalyst was different. Highly dispersed Ni species, small Ni crystallite size, and strong metal-support interaction were presented in the Ni/Al2O3 catalysts with Ni(NO3)2·6H2O and NiSO4·6H2O as nickel sources. Evaluation results showed that the catalyst prepared with Ni(NO3)2·6H2O exhibited higher activity and stability, with CH4 and CO2 conversions of 31.21 and 48.97%. Carbon deposition analysis demonstrated that the catalyst prepared with NiSO4·6H2O contained more graphite carbon.

Outcome after a new porous tantalum rod implantation for treatment of early-stage femoral head osteonecrosis.

BACKGROUND: Tantalum rods have been used in osteonecrosis of the femoral head (ONFH) for several years, while Zimmer trabecular metal implants have been proposed as the best choice. The aim of this study was to evaluate the effect of a new porous tantalum rod on the treatment of early ONFH. METHODS: From July 2014 to December 2015, 19 patients (21 hips) were treated with Runze tantalum rod, and 20 patients (20 hips) received Zimmer tantalum prosthesis. All patients were followed up for at least 3 years. RESULTS: There was no significant difference in demographic characteristics and the Harris Hip Score (HHS) improvement between the two groups. Kaplan-Meier analysis did not show any statistically significant difference in survival rates. One case in the Runze group had persistent pain and required conversion to total hip arthroplasty (THA) 8 months post-surgery. Histological evaluations revealed the presence of abundant new bone ingrowth into pores of the tantalum. The osteonecrosis observed in other patients was almost unchanged. At final follow-up, progressive collapse of the femoral head or the apparent joint space narrowing had not occurred. CONCLUSIONS: Compared with the traditional implants, implantation of the Chinese tantalum rod in the treatment of Association Research Circulation Osseous (ARCO) stages I, and II ONFH demonstrated highly encouraging clinical results.

[Novel nano-hydroxyapatite/polyurethane composite scaffold in the treatment of chronic osteomyelitis].

Objective: To evaluate the bone repair efficacy of the new nano-hydroxyapatite (n-HA)/polyurethane (PU) composite scaffold in the treatment of chronic osteomyelitis in tibia. Methods: A novel levofloxacin@mesoporous silica microspheres (Lev@MSNs)/n-HA/PU was successfully synthesized. Its surface structure was observed by scanning electron microscopy (SEM). Fifty adult female New Zealand rabbits were randomly selected, and osteomyelitis was induced in the right tibia of the rabbit by injecting bacterial suspension ( Staphylococcus aureus; 3×10 7 CFU/mL), which of the method was described by Norden. A total of 45 animals with the evidence of osteomyelitis were randomly divided into 4 groups, and the right medullary cavity of each animal was exposed. Animals in the blank control group (group A, n=9) were treated with exhaustive debridement only. The remaining animals were first treated by exhaustive debridement, and received implantations of 5 mg Lev@PMMA (group B, n=12), 1 mg Lev@MSNs/n-HA/PU (group C, n=12), and 5 mg Lev@MSNs/n-HA/PU (group D, n=12), respectively. At 12 weeks postoperatively, the right tibia of rabbits were observed by X-ray film, and then gross observation, methylene blue/acid fuchsin staining, and SEM observation of implant-bone interface, as well as biomechanical test (measuring the maximal compression force) were performed. Results: X-ray films showed that the infection were severer than those of preoperation in group A, while the control of inflammation and bone healing of rabbits in group D were obviously better than those at preoperation. The gross observation showed extensive bone destruction in group A, a significant gap between bone tissue and the material in groups B and C, and close combination between bone tissue and the material in group D. The histology of the resected specimens showed that there was no obvious new bone formation around the materials in groups B and C, and there was abundant new bone formation around the periphery and along the voids of the materials and active bone remodeling in group D. The SEM observation of the bone-implant interface demonstrated that no new bone formation was observed at the bone-implant interface in groups B and C. However, bony connections and blurred boundaries were observed between the material and host bone tissue in group D. The biomechanical test showed the maximal compression force of groups B and D were significantly higher than that of groups A and C ( P<0.05), but there was no significant difference between groups B and D ( P>0.05). Conclusion: The novel synthetic composite Lev@MSNs/n-HA/PU exhibit good antibacterial activities, osteoconductivity, and biomechanical properties, and show great potential in the treatment of chronic osteomyelitis of rabbits.