Discovery of highly efficient CRBN-recruiting HPK1-PROTAC as a potential chemical tool for investigation of scaffolding roles in TCR signaling.

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a promising target for immune-oncology therapy. It has been recently demonstrated that loss of HPK1 kinase activity can enhance T cell receptor (TCR) signaling. However, many essential functions mediated by the HPK1 scaffolding role are still beyond the reach of any kinase inhibitor. Proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for pathogenic proteins degradation with the characteristics of rapid, reversible, and low-cost versus RNA interference or DNA knock-out technology. Herein we first disclosed the design, synthesis, and evaluation of a series of thalidomide-based PROTAC molecules and identified B1 as a highly efficient HPK1 degrader with DC50 value of 1.8 nM. Further mechanism investigation demonstrated that compound B1 inhibits phosphorylation of the SLP76 protein with IC50 value of 496.1 nM, and confirmed that B1 is a bona fide HPK1-PROTAC degrader. Thus, this study provides a basis for HPK1 degraders development and the candidate could be used as a potential chemical tool for further investigation of the kinase-independent signaling of HPK1 in TCR.

The progress of small molecules against cannabinoid 2 receptor (CB2R).

The two subtypes of cannabinoid receptors (CBR), namely CB1R and CB2R, belong to the G protein-coupled receptor (GPCR) superfamily and are confirmed as potential therapeutic targets for a variety of diseases such as inflammation, neuropathic pain, and immune-related disorders. Since CB1R is mainly distributed in the central nervous system (CNS), it could produce severe psychiatric adverse reactions and addiction. In contrast, CB2R are predominantly distributed in the peripheral immune system with minimal CNS-related side effects. Therefore, more attention has been devoted to the discovery of CB2R ligands. In view of the favorable profile of CB2R, many high-binding affinity and selectivity CB2R ligands have been developed recently. This paper reviews recent research progress on CB2R ligands, including endogenous CB2R ligands, natural compounds, and novel small molecules, in order to provide a reference for subsequent CB2R ligand development.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Discovery of novel pyrrolo [2,3-d] pyrimidine derivatives as potent FAK inhibitors based on cyclization strategy.

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a pivotal role in tumor invasion and metastasis. Many FAK inhibitors had been reported, but the development of FAK inhibitors in clinical studies are still limited. To facilitate the discovery of FAK modulators and further elucidate the role of FAK in cancer metastasis, it is necessary to discover a novel, potent and selective FAK inhibitor. In this study, a series of FAK inhibitors with novel scaffold were designed and synthesized based on cyclization strategy. Here, we reported compound 10b (HMC-18NH) with excellent inhibition of FAK (IC50 = 9.9 nM) and anticancer activity against several cancer cell lines including BxPC-3, PANC-1, MCF-7, MDA-MB-231, U-87MG, HepG2, HCT-15 and A549. Extraordinary, compound 10b showed the best cytotoxic effects against A549 with the IC50 value of 0.8 µM. In addition, 10b exhibited effective invasion and migration suppression in A549 cells. Further investigations revealed that compound 10b potently induced and promoted apoptosis in a dose-dependent manner and arrested A549 cells in the G2/M phase. Collectively, these results suggest that 10b is a promising FAK inhibitor and serve as a lead compound which deserve for further optimization.

Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.

Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC50 = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC50 = 283.0 nM) and promotion IL-2 release (EC50 = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T1/2 = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.

A Novel Diagnosis Method Based on Methylation Analysis of SHOX2 and Serum Biomarker for Early Stage Lung Cancer.

OBJECTIVES: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule. METHODS: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases. RESULTS: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627-0.816), 0.753 (95% CI: 0.673-0.833) and 0.778(95% CI: 0.700-0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers. CONCLUSIONS: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.

HZ-A-005, a potent, selective, and covalent Bruton's tyrosine kinase inhibitor in preclinical development.

Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec kinases family and is essential for B cell receptor (BCR) mediated signaling. BTK inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. Here we disclose a potent, selective, and covalent BTK inhibitor, HZ-A-005, currently in preclinical development. HZ-A-005 demonstrated dose-dependent activity in two xenograft models of lymphoma in vivo. It showed highly favourable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical studies. On the basis of its potency, selectivity, and covalent mode of inhibition, HZ-A-005 reveals the potential to be a promising BTK inhibitor for a wide range of cancer indications.

Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1).

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

An Aseptic One-Shot Bottom-Up Method To Produce Progesterone Nanocrystals: Controlled Size and Improved Bioavailability.

Progesterone (PG) is an essential sex hormone with a variety of important biological functions, but its insolubility leads to low bioavailability of most water-based formulations. What is more, the commercial oil-based formulations often cause severe side effects after long-term injection due to poor tissue absorption of oil. Herein, we report an aseptic bottom-up method utilizing emulsion freeze-drying technology that produces size-controllable, highly bioavailable, and water-based PG nanocrystal injection. The key factors that can determine the features of nanocrystals were investigated, including solvents, water-to-oil ratio, drug concentrations, type of surfactants, temperature in freeze-drying process, and lyoprotectants. Mechanisms of crystal growth formation process for PG nanocrystals were also analyzed theoretically. The prepared water-based PG nanocrystal suspension injection (PG/NSI) not only showed quick dissolution behaviors but also had significantly improved bioavailability in vivo. Therefore, this method can effectively control the size of nanocrystals, enhance bioavailability of insoluble drugs, and produce aseptic water-based nanocrystals that can be directly used for injection. Moreover, this method can also be used to prepare nanocrystals with the desired size under aseptic conditions for other poorly water-soluble drugs.

Discovery of novel coumarin derivatives as potent and orally bioavailable BRD4 inhibitors based on scaffold hopping.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.

Antifibrotic effects of a novel pirfenidone derivative in vitro and in vivo.

BACKGROUND: Idiopathic pulmonary fibrosis is a lethal fibrosing interstitial pneumonia characterized by progressive worsening of dyspnea and lung function with poor prognosis. Since pirfenidone was approved for IPF treatment, the search for more effective candidates has been greatly intensified. METHODS: In this study, the antifibrotic effects and mechanisms of compound PBD-617, the ideal candidate discovered in our previous work, were investigated on transforming growth factor-ß1 (TGF-ß1)-induced human embryonic lung fibroblasts (HELF) and on bleomycin (BLM)-induced pulmonary fibrotic rats. RESULTS: Oral administration with PBD-617 decreased the levels of collagen I, collagen III and matrix metalloproteinase 7, and inhibited the protein expression of α-smooth muscle actin in BLM-induced pulmonary fibrosis rats. Furthermore, PBD-617 suppressed the expression of TGF-ß1, phosphorylated Smad3, phosphorylated p38 and activator protein 1 on TGF-ß1-induced HELF, while the regulation could be rescued by using p38 agonist p79350. CONCLUSION: PBD-617 not only inhibited TGF-ß1-induced HELF proliferation, but also attenuated BLM-induced pulmonary fibrosis in rats, with efficacy to some extent higher than that of pirfenidone at the same effective dosage. PBD-617 attenuated pulmonary fibrosis effectively by suppressing activation of TGF-ß1/Smad3 and p38 signaling pathways.

Butein Inhibited In Vitro Hexokinase-2-Mediated Tumor Glycolysis in Hepatocellular Carcinoma by Blocking Epidermal Growth Factor Receptor (EGFR).

BACKGROUND Anaerobic glycolysis is an important physiological process of all cancer cells. Butein has been reported to demonstrate substantial antitumor activities in various cancers. However, the effect of butein on tumor glycolysis remains unclear. In this study, the effect of butein on tumor glycolysis and the underlying mechanism were investigated in hepatocellular carcinoma (HCC). MATERIAL AND METHODS Cell proliferation assay and anchorage-independent growth assay were carried out to evaluate the antitumor activities of butein in vitro. The effect of butein on tumor glycolysis was determined by examining the changes in glucose uptake and lactate production. Hexokinase-2 (HK-2) expression in HCC cells upon butein treatment was analyzed by Western blotting. The activity of butein on EGFR signaling pathway was studied and its potency in EGFR exogenous overexpression cells was investigated. RESULTS After butein treatment, HCC cell proliferation was significantly inhibited (91.4% in Hep3B and 88.2% in Huh-7 at 80 µM, p<0.001). Moreover, the number of colonies formed in the agar was substantially decreased (93.8% in Hep3B and 72.3% in Huh-7 at 80 µM, p<0.001). With the suppression of HK-2 expression, glucose consumption in Hep3B and Huh-7 cells decreased by 48.4% and 56.3%, respectively (p<0.01), and the lactate production also was reduced accordingly (39.5% in Hep3B and 48.6% in Huh-7, p<0.01). Mechanism investigations demonstrated that butein dose-dependently blocked the activation of the EGFR signaling pathway in HCC cells. In EGFR exogenous overexpression cells, the glycolysis suppression exerted by butein was substantially attenuated. CONCLUSIONS Butein has a substantial inhibitory effect on tumor glycolysis in HCC cells, and the glycolysis suppression exerted by butein is closely related to its effect on the EGFR signaling pathway.

On-line biofilm strength detection in cross-flow membrane filtration systems.

A fluid dynamic gauging (FDG) technique was used for on-line and in situ measurements of Pseudomonas aeruginosa PAO1 biofilm thickness and strength on flat sheet polyethersulphone membranes. The measurements are the first to be successfully conducted in a membrane cross-flow filtration system under constant permeation. In addition, FDG was used to demonstrate the removal behaviour of biofilms through local biofilm strength and removal energy estimation, which other conventional measurements such as flux and TMP cannot provide. The findings suggest that FDG can provide valuable additional information related to biofilm properties that have not been measured by other monitoring methods.

Phospholipid Phosphatase 4 promotes proliferation and tumorigenesis, and activates Ca2+-permeable Cationic Channel in lung carcinoma cells.

BACKGROUND: Phospholipid phosphatase 4 (PPAPDC1A or PLPP4) has been demonstrated to be involved in the malignant process of many cancers. The purpose of this study was to investigate the clinical significance and biological roles of PLPP4 in lung carcinoma. METHODS: PLPP4 expression was examined in 8 paired lung carcinoma tissues by real-time PCR and in 265 lung carcinoma tissues by immunohistochemistry (IHC). Statistical analysis was performed to evaluate the clinical correlation between PLPP4 expression and clinicopathological features and survival in lung carcinoma patients. In vitro and in vivo assays were performed to assess the biological roles of PLPP4 in lung carcinoma. Fluorescence-activated cell sorting, Western blotting and luciferase assays were used to identify the underlying pathway through which PLPP4 silencing mediates biological roles in lung carcinoma. RESULTS: PLPP4 is differentially elevated in lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SQC) tissues. Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients. Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells. Our results further reveal that PLPP4 silencing inhibits Ca2+-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular Ca2+. CONCLUSION: Our results indicate that PLPP4 may hold promise as a novel marker for the diagnosis of lung carcinoma and as a potential therapeutic target to facilitate the development of novel treatment for lung carcinoma.

Evaluation of HE4 in the Diagnosis and Follow Up of Non-Small Cell Lung Cancers.

BACKGROUND: The aim of our study was to evaluate the performance of HE4 in the diagnosis and follow up in patients with non-small cell lung cancer (NSCLC). METHODS: Serum levels of HE4, CEA, and Cyfra 21-1 were analyzed in 146 patients suspected with NSCLC and 30 healthy subjects to evaluate their diagnostic performance. A one year follow up was performed in 61 patients confirmed with NSCLC after surgery eradication at the interval of 1 month, 3 months, 6 months, and 12 months. RESULTS: Our results showed that the area under the receiver operating characteristics curve (AUC) of HE4 was 0.761, which was similar with CEA. The sensitivity and specificity of HE4 was 0.82 and 0.62, respectively, at the level of 75.0 pmol/L. The AUC of HE4 was 0.70, 0.81, and 0.90 at 1 month, 3 months, and 6 months after surgery, respectively, which was significantly higher than CEA and Cyfra 21-1. CONCLUSIONS: Our finding indicates that HE4 is a potential marker for the diagnosis and follow up of NSCLC patients, which is complementary with CEA and Cyfra 21-1 and accurate in predicting NSCLC recurrence in early stage.

Three new alkaloids from Veratrum grandiflorum Loes with inhibition activities on Hedgehog pathway.

Three new steroidal alkaloids 1-3, together with four known compounds 4-7, were isolated from the ethanol extract of Veratrum grandiflorum Loes. Their structures were elucidated by NMR (1D and 2D NMR) and MS spectroscopic data. The inhibition activities on Hedgehog (Hh) pathway were evaluated using a cell-based bioassay system (Shh-LIGHT 2 cells). The results showed that compounds 1-3 and 5 displayed inhibitory activities obviously with the IC50 values of 0.63-3.11µM. Among them, compound 5 showed the most prominent inhibition activity (IC50=0.63±0.02µM). Thus, these active alkaloids may be potent natural compounds as Hh pathway inhibitors for the treatment of various cancers.

Comparison of Borate Bioactive Glass and Calcium Sulfate as Implants for the Local Delivery of Teicoplanin in the Treatment of Methicillin-Resistant Staphylococcus aureus-Induced Osteomyelitis in a Rabbit Model.

There is growing interest in biomaterials that can cure bone infection and also regenerate bone. In this study, two groups of implants composed of 10% (wt/wt) teicoplanin (TEC)-loaded borate bioactive glass (designated TBG) or calcium sulfate (TCS) were created and evaluated for their ability to release TEC in vitro and to cure methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis in a rabbit model. When immersed in phosphate-buffered saline (PBS), both groups of implants provided a sustained release of TEC at a therapeutic level for up to 3 to 4 weeks while they were gradually degraded and converted to hydroxyapatite. The TBG implants showed a longer duration of TEC release and better retention of strength as a function of immersion time in PBS. Infected rabbit tibiae were treated by debridement, followed by implantation of TBG or TCS pellets or intravenous injection with TEC, or were left untreated. Evaluation at 6 weeks postimplantation showed that the animals implanted with TBG or TCS pellets had significantly lower radiological and histological scores, lower rates of MRSA-positive cultures, and lower bacterial loads than those preoperatively and those of animals treated intravenously. The level of bone regeneration was also higher in the defects treated with the TBG pellets. The results showed that local TEC delivery was more effective than intravenous administration for the treatment of MRSA-induced osteomyelitis. Borate glass has the advantages of better mechanical strength, more desirable kinetics of release of TEC, and a higher osteogenic capacity and thus could be an effective alternative to calcium sulfate for local delivery of TEC.

Discovery of Novel Selective ERα/ERß Ligands by Multi-pharmacophore Modeling and Virtual Screening.

Estrogen receptor α (ERα) and estrogen receptor ß (ERß) regulate different sets of gene expression, and have different ligand responses, which make the estrogen tissue-specific. Thus, the estrogen receptor (ER) subtype-selective ligands can improve the target-site selectivity and decrease the off-target effect. In order to discover the selective ER subtype ligands with novel scaffolds, in this work three-dimensional (3D) pharmacophore models of the ERα ligands (Hypo 1) and the ERß ligands (Hypo 2) were established (correlation coefficients were 0.959 and 0.966) and validated (R=0.936 and 0.879; enrichment factors (EFs) at 2% were 16.2 and 8.4; areas under the concentration-time curve (AUC) of the receiver operating curve (ROC) were 0.88 and 0.91) using the Discovery Studio 4.0 software package. Hypo 1 and Hypo 2 were then employed for virtual screening and ten hits were found as potential candidate leads. Based on their ERα/ERß binding affinity results by fluorescence polarization technology, two of these leads, AH-262/34334025 (AH) and AG-670/08803023 (AG) with novel scaffolds were identified as selective ERα ligands. A molecular docking study was also performed, which provided the explanation for the ER subtype preferences for AH and AG.

Synthesis and biological evaluation of the pirfenidone derivatives as antifibrotic agents.

A total of 24 pirfenidone derivatives were designed, synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. These compounds showed the remarkable proliferation inhibition against MRC-5 compared to pirfenidone as the positive control. The possible mechanism of this kind of derivatives as antifibrotic agents was explored. The molecular docking and p38 binding affinity assays demonstrated that the antifibrotic potential of the pirfenidone derivatives was possibly through the inhibition of p38 MAPK signaling pathway. The data from this study suggested that p38 might be a potential therapeutic target for the new generation antifibrotics. All the pirfenidone derivatives are reported here for the first time.

A novel injectable borate bioactive glass cement for local delivery of vancomycin to cure osteomyelitis and regenerate bone.

Osteomyelitis (bone infection) is often difficult to cure. The commonly-used treatment of surgical debridement to remove the infected bone combined with prolonged systemic and local antibiotic treatment has limitations. In the present study, an injectable borate bioactive glass cement was developed as a carrier for the antibiotic vancomycin, characterized in vitro, and evaluated for its capacity to cure osteomyelitis in a rabbit tibial model. The cement (initial setting time = 5.8 ± 0.6 min; compressive strength = 25.6 ± 0.3 MPa) released vancomycin over ~25 days in phosphate-buffered saline, during which time the borate glass converted to hydroxyapatite (HA). When implanted in rabbit tibial defects infected with methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis, the vancomycin-loaded cement converted to HA and supported new bone formation in the defects within 8 weeks. Osteomyelitis was cured in 87 % of the defects implanted with the vancomycin-loaded borate glass cement, compared to 71 % for the defects implanted with vancomycin-loaded calcium sulfate cement. The injectable borate bioactive glass cement developed in this study is a promising treatment for curing osteomyelitis and for regenerating bone in the defects following cure of the infection.