查看更多>>摘要：Since accelerated metabolism produces much higher levels of reactive oxygen species(ROS)in cancer cells compared to ROS levels found in normal cells,human MutT homolog 1(MTH1),which san-itizes oxidized nucleotide pools,was recently demonstrated to be crucial for the survival of cancer cells,but not required for the proliferation of normal cells.Therefore,dozens of MTH 1 inhibitors have been devel-oped with the aim of suppressing cancer growth by accumulating oxidative damage in cancer cells.While several inhibitors were indeed confirmed to be effective,some inhibitors failed to kill cancer cells,compli-cating MTH1 as a viable target for cancer eradication.In this review,we summarize the current status of developing MTH1 inhibitors as drug candidates,classify the MTH1 inhibitors based on their structures,and offer our perspectives toward the therapeutic potential against cancer through the targeting of MTH 1.
查看更多>>摘要：Multiple cancer immunotherapies including chimeric antigen receptor T cell and immune checkpoint inhibitors(ICIs)have been successfully developed to treat various cancers by motivating the adaptive anti-tumor immunity.Particularly,the checkpoint blockade approach has achieved great clinic success as evidenced by several U.S.Food and Drug Administration(FDA)-approved anti-programmed death receptor 1/ligand 1 or anti-cytotoxic T lymphocyte associated protein 4 antibodies.However,the majority of cancers have low clinical response rates to these ICIs due to poor tumor immu-nogenicity.Indeed,the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-TANK-binding kinase 1(cGAS-STING-TBK1)axis is now appreciated as the major signaling pathway in innate immune response across different species.Aberrant signaling of this pathway has been closely linked to multiple diseases,including auto-inflammation,virus infection and cancers.In this perspective,we provide an updated review on the latest progress on the development of small mole-cule modulators targeting the cGAS-STING-TBKl signaling pathway and their preclinical and clinical use as a new immune stimulatory therapy.Meanwhile,highlights on the clinical candidates,limitations and challenges,as well as future directions in this field are also discussed.Further,small molecule inhib-itors targeting this signaling axis and their potential therapeutic use for various indications are discussed as well.
查看更多>>摘要：Programmed cell death-1(PD-1)/programmed cell death ligand-1(PD-L1)blocking ther-apy has become a major pillar of cancer immunotherapy.Compared with antibodies targeting,small-molecule checkpoint inhibitors which have favorable pharmacokinetics are urgently needed.Here we identified berberine(BBR),a proven anti-inflammation drug,as a negative regulator of PD-L1 from a set of traditional Chinese medicine(TCM)chemical monomers.BBR enhanced the sensi-tivity of tumour cells to co-cultured T-cells by decreasing the level of PD-Ll in cancer cells.In addi-tion,BBR exerted its antitumor effect in Lewis tumor xenograft mice through enhancing tumor-infiltrating T-cell immunity and attenuating the activation of immunosuppressive myeloid-derived sup-pressor cells(MDSCs)and regulatory T-cells(Tregs).BBR triggered PD-L1 degradation through ubi-quitin(Ub)/proteasome-dependent pathway.Remarkably,BBR selectively bound to the glutamic acid 76 of constitutive photomorphogenic-9 signalosome 5(CSN5)and inhibited PD-1/PD-Ll axis through its deubiquitination activity,resulting in ubiquitination and degradation of PD-L1.Our data reveals a previously unrecognized antitumor mechanism of BBR,suggesting BBR is small-molecule immune checkpoint inhibitor for cancer treatment.
查看更多>>摘要：Prostate cancer(PCa)patients who progress to metastatic castration-resistant PCa(mCRPC)mostly have poor outcomes due to the lack of effective therapies.Our recent study established the orphan nuclear receptor RORγ as a novel therapeutic target for CRPC.Here,we reveal that elaiophylin(Elai),an antibiotic from Actinomycete streptomyces,is a novel RORγ antagonist and showed potent antitumor ac-tivity against CRPC in vitro and in vivo.We demonstrated that Elai selectively binded to RORγ protein and potently blocked RORy transcriptional regulation activities.Structure-activity relationship studies showed that Elai occupied the binding pocket with several key interactions.Furthermore,Elai markedly reduced the recruitment of RORy to its genomic DNA response element(RORE),suppressed the expres-sion of RORγ target genes AR and AR variants,and significantly inhibited PCa cell growth.Importantly,Elai strongly suppressed tumor growth in both cell line based and patient-derived PCa xenograft models.Taken together,these results suggest that Elai is novel therapeutic RORy inhibitor that can be used as a drug candidate for the treatment of human CRPC.
查看更多>>摘要：Herpes simplex virus type 1(HSV-1)is a ubiquitous and widespread human pathogen,which gives rise to a range of diseases,including cold sores,corneal blindness,and encephalitis.Currently,the use of nucleoside analogs,such as acyclovir and penciclovir,in treating HSV-1 infection often presents limi-tation due to their side effects and low efficacy for drug-resistance strains.Therefore,new anti-herpetic drugs and strategies should be urgently developed.Here,we reported that baicalein,a naturally derived compound widely used in Asian countries,strongly inhibited HSV-1 replication in several models.Baica-lein was effective against the replication of both HSV-1/F and HSV-1/Blue(an acyclovir-resistant strain)in vitro.In the ocular inoculation mice model,baicalein markedly reduced in vivo HSV-1/F replication,receded inflammatory storm and attenuated histological changes in the cornea.Consistently,baicalein was found to reduce the mortality of mice,viral loads both in nose and trigeminal ganglia in HSV-1 intra-nasal infection model.Moreover,an ex vivo HSV-1-EGFP infection model established in isolated murine epidermal sheets confirmed that baicalein suppressed HSV-1 replication.Further investigations unraveled that dual mechanisms,inactivating viral particles and inhibiting IκB kinase beta(IKK-β)phosphorylation,were involved in the anti-HSV-1 effect of baicalein.Collectively,our findings identified baicalein as a promising therapy candidate against the infection of HSV-1,especially acyclovir-resistant strain.
查看更多>>摘要：Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hyperten-sion(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10A inhibitor,14-3HC1(half maximal inhibitory concentration,IC50 = 2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50％was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14-3HC1[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment.The crystal structure of the PDE10A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10A inhibitors.
查看更多>>摘要：Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92 ± 1.33％)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which conse-quently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,co-administering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89％of tumor suppression in 4T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nano-particles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.
查看更多>>摘要：The short release half-life of carbon monoxide(CO)is a major obstacle to the effective ther-apeutic use of carbon monoxide-releasing molecule-2(CORM-2).The potential of CORM-2-entrapped ultradeformable liposomes(CORM-2-UDLs)to enhance the release half-life of CO and alleviate skin inflammation was investigated in the present study.CORM-2-UDLs were prepared by using soy phospha-tidylcholine to form lipid bilayers and Tween 80 as an edge activator.The deformability of CORM-2-UDLs was measured and compared with that of conventional liposomes by passing formulations through a filter device at a constant pressure.The release profile of CO from CORM-2-UDLs was evaluated by myoglobin assay.In vitro and in vivo anti-inflammatory effects of CORM-2-UDLs were assessed in lipopolysaccharide-stimulated macrophages and TPA-induced ear edema model,respectively.The deformability of the optimized CORM-2-UDLs was 2.3 times higher than conventional liposomes.CORM-2-UDLs significantly prolonged the release half-life of CO from 30 s in a CORM-2 solution to 21.6 min.CORM-2-UDLs demonstrated in vitro anti-inflammatory activity by decreasing nitrite pro-duction and pro-inflammatory cytokine levels.Furthermore,CORM-2-UDLs successfully ameliorated skin inflammation by reducing ear edema,pathological scores,neutrophil accumulation,and inflamma-tory cytokines expression.The results demonstrate that CORM-2-UDLs could be used as promising ther-apeutics against acute skin inflammation.
查看更多>>摘要：The radiotherapy modulators used in clinic have disadvantages of high toxicity and low selectivity.For the first time,we used the in situ enzyme-instructed self-assembly(EISA)of a peptide derivative(Nap-GDFDFpYSV)to selectively enhance the sensitivity of cancer cells with high alkaline phosphatase(ALP)expression to ionizing radiation(IR).Compared with the in vitro pre-assembled con-trol formed by the same molecule,assemblies formed by in situ EISA in cells greatly sensitized the ALP-high-expressing cancer cells to γ-rays,with a remarkable sensitizer enhancement ratio.Our results indi-cated that the enhancement was a result of fixing DNA damage,arresting cell cycles and inducing cell apoptosis.Interestingly,in vitro pre-formed assemblies mainly localized in the lysosomes after incubating with cells,while the assemblies formed via in situ EISA scattered in the cell cytosol.The accumulation of these molecules in cells could not be inhibited by endocytosis inhibitors.We believed that this molecule entered cancer cells by diffusion and then in situ self-assembled to form nanofibers under the catalysis of endogenous ALP.This study provides a successful example to utilize intracellular in situ EISA of small molecules to develop selective tumor radiosensitizers.
查看更多>>摘要：The"vicious cycle"established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis,leading to life-threatening skeletal-related events that severely reduce survival and quality of life.To effectively interrupt the"vicious cycle",innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed.Herein,a bone-seeking moiety,alendronate(ALN),functionalized coordination polymer nanoparticles(DZ@ALN)co-delivering cisplatin prodrug(DSP)and antiresorptive agent zoledronate(ZOL)via Zn2+crosslinking for combina-tion therapy was reported.The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries,and possesses an excellent bone-seeking ability both in vitro and in vivo.Additionally,DZ@ALN could synergistically inhibit the proliferation of cancer cells,suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro.Importantly,it could preferentially accumulate in bone affected site,remarkably inhibit the proliferation of tumor cells,relieving bone pain,and significantly inhibit the activation of osteoclasts,protecting the bone from destruction in vivo,eventually leading to the breakdown of"vicious cycle"without inducing obvious sys-temic toxicity.This innovative nanoagent combines chemotherapy and osteolysis inhibition,exhibiting an inspiring strategy for effective treatment of bone metastasis.
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