Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.

Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones.

The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2 as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.

Sarcopenia predicts prognosis of patients with renal cell carcinoma: A systematic review and meta-analysis.

Sarcopenia, a concept reflecting the loss of skeletal muscle mass, was reported to be associated with the prognosis of several tumors. However, the prognostic value of sarcopenia in patients with renal cancer remains unclear. We carried out this meta-analysis and systematic review to evaluate the prognostic value of sarcopenia in patients with renal cell carcinomas. We comprehensively searched PubMed, Embase, and Cochrane Library from inception to December 2018. Hazard ratio (HR) and 95% confidence interval (CI) were pooled together. A total of 5 studies consisting of 771 patients were enrolled in this quantitative analysis, 347 (45.0%) of which had sarcopenia. Patients with sarcopenia had a worse OS compared with those without sarcopenia (HR=1.76; 95%CI, 1.35-2.31; P<0.001). In the subgroup of patients with localized and advanced/metastatic diseases, sarcopenia was also associated with poor OS (HR=1.48, P=0.039; HR=2.14, P<0.001; respectively). With a limited sample size, we did not observe difference of PFS between two groups (HR=1.56, 95% CI, 0.69-3.50, P=0.282). In the present meta-analysis, we observed that patients with sarcopenia had a worse OS compared with those without sarcopenia in RCC. Larger, preferably prospective studies, are needed to confirm and update our findings.

Positioning Locality Using Cognitive Directions Based on Indoor Landmark Reference System.

Locality descriptions are generally communicated using reference objects and spatial relations that reflect human spatial cognition. However, uncertainty is inevitable in locality descriptions. Positioning locality with locality description, with a mapping mechanism between the qualitative and quantitative data, is one of the important research issues in next-generation geographic information sciences. Spatial relations play an important role in the uncertainty of positioning locality. In indoor landmark reference systems, the nearest landmarks can be selected when describing localities by using direction relations indoors. By using probability operation, we combine a set of uncertainties, that is, near and direction relations to positioning locality. Some definitions are proposed from cognitive and computational perspectives. We evaluate the performance of our method through indoor cognitive experiments. Test results demonstrate that a positioning accuracy of 3.55 m can be achieved with the semantically derived direction relationships in indoor landmark reference systems.

4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.

The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8 µg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.

SAR exploration at the C-3 position of tetrahydro-ß-carboline sstr3 antagonists.

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Cascaded-TOARNet: A cascaded framework based on mixed attention and multiscale information for thoracic OARs segmentation.

BACKGROUND: Accurate and automated segmentation of thoracic organs-at-risk (OARs) is critical for radiotherapy treatment planning of thoracic cancers. However, this has remained a challenging task for four major reasons: (1) thoracic OARs have diverse morphologies; (2) thoracic OARs have low contrast with the background; (3) boundaries of thoracic OARs are blurry; (4) class imbalance issue caused by small organs. PURPOSE: To overcome the above challenges and achieve accurate and automated segmentation of thoracic OARs on thoracic CT. METHODS: A novel cascaded framework based on mixed attention and multiscale information for thoracic OARs segmentation, called Cascaded-TOARNet. This cascaded framework comprises two stages: localization and segmentation. During the localization stage, TOARNet locates each organ to crop the regions of interest (ROIs). During the segmentation stage, TOARNet accurately segments the ROIs, and the segmentation results are merged into a complete result. RESULTS: We evaluated our proposed method and other common segmentation methods on two public datasets: the AAPM Thoracic Auto-Segmentation Challenge dataset and the Segmentation of Thoracic Organs at Risk (SegTHOR) dataset. Our method demonstrated superior performance, achieving a mean Dice score of 92.6% on the SegTHOR dataset and 90.8% on the AAPM dataset. CONCLUSIONS: This segmentation method holds great promise as an essential tool for enhancing the efficiency of thoracic radiotherapy planning.

[Dynamic study of correspondence of prescription and syndrome system: a system with combination of disease and syndrome, correspondence of prescription and syndrome].

By analyzing the present situation and existing problems in the material bases of syndrome and Chinese materia medica, we think that either syndrome or prescription is a complex whole system. Studies of the material bases of syndrome and prescription should be established on the combination of disease and syndrome, following the holistic and dynamic principles. Departure from the holistic principle, separating the syndrome from the prescription, ignoring the dynamic concepts may possibly lose the features and advantages of syndrome typing and Chinese medicine preparations. The metabolomics research bridges the study of prescription and syndrome. It is of great significance in finding out the agreeable point of disease-syndrome-efficacy, establishing a dynamic research method with combination of disease and syndrome, correspondence of prescription and syndrome.

Advances in AR-targeting chimeras: a case study of proteolysis-targeting chimeras from bench to bedside.

Proteolysis-targeting chimera (PROTAC) is an emerging revolutionary technology that promotes degradation of target proteins by proteolysis. AR-targeting PROTACs marked many milestones in the history of PROTAC development. In this review, the author discusses the development of AR-targeting PROTACs over the last two decades. Also included in this focused review are medicinal chemistry strategies, pharmacokinetic profiles and clinical development. Taking AR targeting PROTACs for case study, this review provides a target specific overview of how PROTAC technology has advanced from a revolutionary concept and achieved proof of concept leading to drug candidates that benefit patients.

D-dimer/fibrinogen ratio for the prediction of progressive hemorrhagic injury after traumatic brain injury.

BACKGROUND: Progressive hemorrhagic injury (PHI) greatly affects prognosis of traumatic brain injury (TBI). D-dimer/fibrinogen ratio (D/F ratio) may be a potential predictor for venous thromboembolism. This study sought to describe and evaluate any relationship between D/F ratio and PHI after TBI. METHODS: This retrospective study included a cohort of 192 TBI patients. Plasma D-dimer and fibrinogen were measured, and subsequently D/F ratio was calculated. Multivariate logistic regression analysis was applied to identify predictors of PHI. Receiver operating characteristic (ROC) curve was conFig.d to analyze predictive capability for PHI. RESULTS: A total of 43 patients (22.4%) experienced PHI. Both Glasgow coma scale (GCS) score (odds ratio [OR], 0.565; 95% CI, 0.464-0.689) and D/F ratio (OR, 4.026; 95% CI, 2.219-7.305) were the two independent predictor for PHI. Area under ROC curve (AUC) of D/F ratio was similar to that of GCS score (AUC, 0.816; 95% CI, 0.754-0.868 vs. AUC, 0.834; 95% CI, 0.773-0.883; P = 0.699). Moreover, D/F ratio significantly improved AUC of GCS score to 0.928 (95% CI, 0.881-0.960; P < 0.001). CONCLUSIONS: D/F ratio was strongly predictive of PHI in the studied cohort and, thereby should be considered in the clinical management of TBI patients.

Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.

Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer.

Androgen receptor (AR) is a crucial driver of prostate cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.

C-reactive Protein Is a Predictor of Prognosis of Prostate Cancer: A Systematic Review and Meta-Analysis.

Increasing evidence suggested that inflammation is associated with the pathogenesis and progression of several solid tumors. This study was conducted to explore the association between C-reactive protein (CRP) and survival of prostate cancer (PCa). An electronic search was completed on the basis of PubMed, Embase and Cochrane Central Register of Controlled Trials. The hazard ratio (HR) and 95% confidence interval (CI) were extracted. Studies evaluating the relation between pretreatment levels of CRP and survival of PCa were included. Sixteen articles incorporating 17,833 patients were eligible for the present meta-analysis. Elevated pretreatment CRP level was significantly associated with poorer overall survival (OS) (HR=1.58, 95% CI 1.31-1.91, P<0.001), cancer-specific survival (CSS) (HR=1.83, 95% CI 1.19-2.80, P=0.006), progression-free survival (PFS) (HR=1.64, 95%CI 1.03-2.61, P=0.036), and biochemical-recurrence free survival (BC-RFS) (HR=1.29, 95% CI 1.11-1.51, P=0.001). Elevated pretreatment serum CRP level is strongly correlated with worse prognosis in patients with PCa, including OS, CSS, PFS and BC-RFS.

Development of selective mono or dual PROTAC degrader probe of CDK isoforms.

Cyclin-dependent kinase (CDK) family members are promising molecular targets in discovering potent inhibitors in disease settings, they function differentially. CDK2, CDK4 and CDK6, directly regulate the cell cycle, while CDK9 primarily modulates the transcription regulation. In discovering inhibitors of these CDKs, toxicity associated with off-target effect on other CDK homologs often posts as a clinical issue and hinders their further therapeutic development. To improve efficacy and reduce toxicity, here, using the Proteolysis Targeted Chimeras (PROTACs) approach, we design and further optimize small molecule degraders targeting multiple CDKs. We showed that heterobifunctional compound A9 selectively degraded CDK2. We also identified a dual-degrader, compound F3, which potently induced degradation of both CDK2 (DC50: 62 nM) and CDK9 (DC50: 33 nM). In human prostate cancer PC-3 cells, compound F3 potently inhibits cell proliferation by effectively blocking the cell cycle in S and G2/M phases. Our preliminary data suggests that PROTAC-oriented CDK2/9 degradation is potentially an effective therapeutic approach.

Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists.

Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd generation of CB1R inverse agonist from the acyclic amide scaffold. We replaced the oxygen linker in taranabant with nitrogen and prepared a series of amino heterocyclic analogs through a divergent synthesis. Although in general, the amine linker gave reduced binding affinity, potent and selective CB1R inverse agonist was identified from the amino heterocycle series. Molecular modeling was applied to study the binding of the amino heterocycle series at CB1 binding site. The in vitro metabolism of representative members was studied and only trace glucuronidation was found. Thus, it suggests that the right hand side of the molecule may not be the appropriate site for glucuronidation.

[Prokaryotic expression, identification and histo-localization of the Taenia asiatica enolase gene].

OBJECTIVE: To express enolase gene of Taenia asiatica, investigate the immunoreactivity of the recombinant TaENO protein, and immuno-histo-localize the presence of the recombinant TaENO in adults of T. asiatica. METHODS: The gene encoding enolase of T. asiatica (TaENO) was cloned by high throughput sequencing from the cDNA library of adult T. asiatica. The coding region of TaENO was amplified by PCR, and cloned into a prokaryotic expression vector pET-30a (+). The recombinant plasmid was transformed into E. coli BL-21/DE3 and followed by expression of the protein induced by IPTG. The protein was purified by Ni-IDA affinity chromatography, and tested by SDS-PAGE. Its immunoreactivity was examined by Western blotting. The mice were immunized subcutaneously with purified TaENO formulated in Freund's adjuvant. Serum samples were collected and analyzed for specific antibodies by ELISA. The localization of TaENO in adult worms was demonstrated by immunofluorescent technique. RESULTS: The recombinant expression plasmid was identified by PCR, double endonuclease digestion and sequencing. The recombinant TaENO was about Mr 47 000 with a concentration of 0.37 mg/ml. It was recognized by antisera of SD rats immunized with TaENO, sera of taeniasis patients and sera of infected swine. The immunofluorescence assay revealed that TaENO immune serum located in the tegument of T. asiatica adult. CONCLUSION: The TaENO gene has been expressed with immunoreactivity, and the recombinant TaENO is immunolocalized in the tegument of T. asiatica adult.

Silver-promoted regioselective [4+2] annulation reaction of indoles with alkenes to construct dihydropyrimidoindolone scaffolds.

An AgI-promoted regioselective [4+2] annulation reaction of indoles with alkenes has been established. During the transformation, N-centered radicals are generated by the oxidation of the N-H bond of N-alkoxyamides. Control experiments and DFT calculations reveal a plausible mechanism. This synergistic process achieves the direct construction of new C-C and C-N bonds under relatively mild conditions with broad substrate scope, high atom economy, and easy-to-handle nature.

BMI1 is a therapeutic target in recurrent medulloblastoma.

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.

Potent and selective alpha-ketoheterocycle-based inhibitors of the anandamide and oleamide catabolizing enzyme, fatty acid amide hydrolase.

A study of the structure-activity relationships (SAR) of 2f (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed, targeting the 5-position of the oxazole. Examination of a series of substituted benzene derivatives (12-14) revealed that the optimal position for substitution was the meta-position with selected members approaching or exceeding the potency of 2f. Concurrent with these studies, the effect of substitution on the pyridine ring of 2f was also examined. A series of small, nonaromatic C5-substituents was also explored and revealed that the K(i) follows a well-defined correlation with the Hammett sigma(p) constant (rho = 3.01, R2 = 0.91) in which electron-withdrawing substituents enhance potency, leading to inhibitors with K(i)s as low as 400 pM (20n). Proteomic-wide screening of the inhibitors revealed that most are exquisitely selective for FAAH over all other mammalian proteases, reversing the 100-fold preference of 20a (C5 substituent = H) for the enzyme TGH.

[Immuno-inflammatory reaction after myocardial infarction and treatment with Chinese and Western medicine].

At present ventricular remodeling (VR) is regarded as the main pathological basis of chronic heart failure after acute myocardial infarction (AMI), and preventing VR after AMI is of great importance for the prevention of heart failure. Previously, it has not been paid enough attention to the role of inflammation and autoimmune injury during the process of VR after AMI. This topic was discussed in the paper and the treating strategies with Chinese and Western medicine were also explored.