RESUMO
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive and devastating disease characterized by pulmonary vascular remodeling which is associated with the malignant phenotypes of pulmonary vascular cells. Recently, the effects of heat shock protein 110 (Hsp110) in human arterial smooth muscle cells were reported. However, the underlying roles and mechanisms of Hsp110 in human pulmonary arterial endothelial cells (HPAECs) that was disordered firstly at the early stage of PAH remain unknown. METHODS: In this research, the expression of Hsp110 in PAH human patients and rat models was investigated, and the Hsp110 localization was determined both in vivo and in vitro. The roles and mechanism of elevated Hsp110 in excessive cell proliferation and migration of HPAECs were assessed respectively exposed to hypoxia. Small molecule inhibitors targeting Hsp110-STAT3 interaction were screened via fluorescence polarization, anti-aggregation and western blot assays. Moreover, the effects of compound 6 on HPAECs abnormal phenotypes in vitro and pulmonary vascular remodeling of hypoxia-indued PAH rats in vivo by interrupting Hsp110-STAT3 interaction were evaluated. RESULTS: Our studies demonstrated that Hsp110 expression was increased in the serum of patients with PAH, as well as in the lungs and pulmonary arteries of PAH rats, when compared to their respective healthy subjects. Moreover, Hsp110 levels were significantly elevated in HPAECs under hypoxia and mediated its aberrant phenotypes. Furthermore, boosted Hsp110-STAT3 interaction resulted in abnormal proliferation and migration via elevating p-STAT3 and c-Myc in HPAECs. Notably, we successfully identified compound 6 as potent Hsp110-STAT3 interaction inhibitor, which effectively inhibited HPAECs proliferation and migration, and significantly ameliorated right heart hypertrophy and vascular remodeling of rats with PAH. CONCLUSIONS: Our studies suggest that elevated Hsp110 plays a vital role in HPAECs and inhibition of the Hsp110-STAT3 interaction is a novel strategy for improving vascular remodeling. In addition, compound 6 could serve as a promising lead compound for developing first-in-class drugs against PAH.
Assuntos
Hipertensão Arterial Pulmonar , Humanos , Ratos , Animais , Hipertensão Arterial Pulmonar/metabolismo , Proteínas de Choque Térmico HSP110/metabolismo , Remodelação Vascular , Células Endoteliais/metabolismo , Hipertensão Pulmonar Primária Familiar , Artéria Pulmonar/patologia , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Proliferação de Células , Fator de Transcrição STAT3/metabolismoRESUMO
Heat shock proteins of 110 kDa (Hsp110s), a unique class of molecular chaperones, are essential for maintaining protein homeostasis. Hsp110s exhibit a strong chaperone activity preventing protein aggregation (the "holdase" activity) and also function as the major nucleotide-exchange factor (NEF) for Hsp70 chaperones. Hsp110s contain two functional domains: a nucleotide-binding domain (NBD) and substrate-binding domain (SBD). ATP binding is essential for Hsp110 function and results in close contacts between the NBD and SBD. However, the molecular mechanism of this ATP-induced allosteric coupling remains poorly defined. In this study, we carried out biochemical analysis on Msi3, the sole Hsp110 in Candida albicans, to dissect the unique allosteric coupling of Hsp110s using three mutations affecting the domain-domain interface. All the mutations abolished both the in vivo and in vitro functions of Msi3. While the ATP-bound state was disrupted in all mutants, only mutation of the NBD-SBDß interfaces showed significant ATPase activity, suggesting that the full-length Hsp110s have an ATPase that is mainly suppressed by NBD-SBDß contacts. Moreover, the high-affinity ATP-binding unexpectedly appears to require these NBD-SBD contacts. Remarkably, the "holdase" activity was largely intact for all mutants tested while NEF activity was mostly compromised, although both activities strictly depended on the ATP-bound state, indicating different requirements for these two activities. Stable peptide substrate binding to Msi3 led to dissociation of the NBD-SBD contacts and compromised interactions with Hsp70. Taken together, our data demonstrate that the exceptionally strong NBD-SBD contacts in Hsp110s dictate the unique allosteric coupling and biochemical activities.
Assuntos
Proteínas de Choque Térmico HSP110/química , Proteínas de Choque Térmico HSP110/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Sítios de Ligação/genética , Candida albicans/genética , Candida albicans/metabolismo , Proteínas de Choque Térmico HSP110/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Nucleotídeos/metabolismo , Ligação Proteica/genética , Domínios Proteicos/genética , Dobramento de ProteínaRESUMO
Homeodomain interacting protein kinase 2 (HIPK2) has emerged as a promising target for the discovery of anti-renal fibrosis drugs. Herein, to develop specific pharmacologic inhibitors of HIPK2, we designed and synthesized a series of compounds containing benzimidazole and pyrimidine scaffolds via fragment-based drug design strategy. Kinase assay was applied to evaluate the inhibitory activity of target compounds against HIPKs enzyme. The molecular docking study suggest the contribution of tyrosine residues beside the active sites of HIPK1-3 to the selectivity of active compounds. Compound 15q displayed good selectivity and potent inhibitory activity against HIPK2 compared to other two subtype enzymes. 15q could downregulate phosphorylated p53, the direct substrate of HIPK2, and decrease the fibrosis-related downstream of HIPK2, such as p-Smad3 and α-SMA in NRK-49F cells. 15q showed no effect on the cell apoptosis in fibrotic or cancer cell lines, suggesting little cancer risk of 15q. Notably, 15q displayed encouraging in vivo anti-fibrotic effects in the unilateral ureteral obstruction mouse model, which could be used as a potential lead for structural optimization and candidate for the development of selective HIPK2 inhibitors.
Assuntos
Apoptose , Proteínas Serina-Treonina Quinases , Animais , Linhagem Celular , Fibrose , Camundongos , Simulação de Acoplamento MolecularRESUMO
A series of novel pyrazolo[3,4-b]pyridine derivatives were designed, synthesized, and biologically evaluated for anti-lung cancer activity. Structure-activity relationship and AutoGPA models were constructed based on the in vitro antiproliferative potency of the compounds against a human lung adenocarcinoma cell line (A549). Compound 9d exhibits improved potency for A549 cell growth inhibition (3.06 ± 0.05 µM) compared with A-769662 (45.29 ± 2.14 µM). Compound 9d can elevate the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) and its substrate acetyl-CoA carboxylase and reduce the level of phosphorylated ribosomal S6 kinase (p-70S6K) at 1 µM, which is comparable to the activity of A-769662 at 20 µM. 9d induced G2/M cell cycle arrest, which was rescued when co-incubated with "Compound C," a potent AMPK inhibitor. Taken together, compound 9d showed potential anti-lung cancer activity via inducing cell cycle arrest by regulation of the AMPK/70S6K pathway in A549 cells, which could provide a new lead for the discovery of anti-lung cancer agents.
Assuntos
Proteínas Quinases Ativadas por AMP , Antineoplásicos , Proteínas Quinases Ativadas por AMP/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Adenosine monophosphate-activated protein kinase (AMPK) plays a key role in maintaining whole-body homeostasis and has been regarded as a therapeutic target for the treatment of diabetic nephropathy (DN). Herein, a series of 1,2,4-oxadiazole-containing pyrazolo[3,4-b]pyridinone derivatives is reported as AMPKÉ1ß1γ1 activators. The in vitro biological assay demonstrated that compounds 12k (EC50 [AMPKα1γ1ß1] = 180 nM) and 13q (EC50 [AMPKα1γ1ß1] = 2 nM) displayed significant enzyme activation. Mechanism studies indicated that both compounds reduced the levels of reactive oxygen species in a rat kidney fibroblast cell line (NRK-49F) stimulated by transforming growth factor-ß and induced early apoptosis of NRK-49F cells at 10 µM. Molecular docking studies suggested that 13q exhibited critical hydrogen-bond interactions with the critical amino acid residues Lys29, Lys31, Asn111, and Asp88 at the binding site of the AMPK protein. These results enrich the structure pool of AMPK activators and provide novel lead compounds for the subsequent development of compounds with a promising therapeutic potential against DN.
Assuntos
Ativadores de Enzimas/farmacologia , Oxidiazóis/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Ativadores de Enzimas/química , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Rim/citologia , Rim/efeitos dos fármacos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Pirazóis/síntese química , Pirazóis/química , Piridonas/síntese química , Piridonas/química , Ratos , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-AtividadeRESUMO
Cisplatin (CP) is one of the most effective chemotherapeutics in the treatment of human cancers. However, the beneficial effects of CP are limited by the toxic effects, especially nephrotoxicity. Fluorofenidone (AKFPD) is a promising multifunctional antifibrosis pyridinone drug discovered by our group. But there is no evidence of its protective effects against acute kidney injury (AKI). Therefore, we investigated the protective effects of AKFPD on CP-induced AKI in vivo and in vitro. Compared with the model group, treatment with AKFPD effectively ameliorated kidney damages. In order to elucidate the mechanisms, we discovered that AKFPD treatment notably alleviated generation of reactive oxygen species, reduced the phosphorylation levels of MAPKs (ERK1 and 2, JNKs, and p38), suppressed inflammatory response, inhibited apoptosis, and abated the expression of CP transporters (organic cation transporter 2 and copper transport protein 1) compared with the model group. Moreover, because renal ischemia reperfusion injury (IRI)-induced AKI and LPS-induced AKI are the major models representative of renal transplantation-correlated AKI and sepsis-related AKI, which are also the main causes of AKI, we have also proved the effectiveness of AKFPD on these models. In conclusion, these findings suggest that AKFPD is a potent drug for CP-, IRI-, and LPS-caused AKI and elucidate the underlying mechanism.-Jiang, Y., Quan, J., Chen, Y., Liao, X., Dai, Q., Lu, R., Yu, Y., Hu, G., Li, Q., Meng, J., Xie, Y., Peng, Z., Tao, L. Fluorofenidone protects against acute kidney injury.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Cisplatino/toxicidade , Piridonas/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular , Transportador de Cobre 1/genética , Transportador de Cobre 1/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Rim/citologia , Rim/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transportador 2 de Cátion Orgânico/genética , Transportador 2 de Cátion Orgânico/metabolismo , Peroxidase/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Traumatismo por ReperfusãoRESUMO
Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied ß adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 µM), compared to propranolol (59.5-75.8 µM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 µM for 5m, partially inhibited at 50 µM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 µM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Reposicionamento de Medicamentos , Melanoma/tratamento farmacológico , Propanóis/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Propanóis/síntese química , Propanóis/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
CD147 is a transmembrane glycoprotein and a member of immunoglobulin superfamily, is strongly expressed in melanoma cells. CD147 has a pivotal role in tumor development. Therefore, it is a potential drug target for melanoma. In this article, we report the discovery of the first CD147 protein proteolysis targeting chimeras (PROTACs) derived from the natural product pseudolaric acid B (PAB). The representative compound 6a effectively induced degradation of CD147 and inhibited melanoma cells in vitro and in vivo. 6a could be used as the novel type of anticancer agent or as a part of the molecular biology research toolkit used in the gain-of-function study of the dynamic roles of CD147 in cancer networks.
Assuntos
Antineoplásicos , Basigina , Diterpenos , Melanoma , Proteólise , Animais , Feminino , Humanos , Camundongos , Alquilação , Antineoplásicos/química , Antineoplásicos/farmacologia , Basigina/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Diterpenos/síntese química , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Melanoma/tratamento farmacológico , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais , Cicatrização/efeitos dos fármacosRESUMO
Bromodomain-containing protein 4 (BRD4), consisting of two tandem bromodomains (BD1 and BD2), is key epigenetic regulator in fibrosis and cancer, which has been reported that BD1 and BD2 have distinct roles in post-translational modification. But there are few selective inhibitors toward those two domains. Herein, this study designed and synthesized a series of novel selective BRD4-BD1 inhibitors, using computer-aided drug design (CADD) approach focused on exploring the difference of the binding pockets of BD1 and BD2, and finding the His437 a crucial way to achieve BRD4-BD1 selectivity. Our results revealed that the compound 3u is a potent selective BRD4-BD1 inhibitor with IC50 values of 0.56⯵M for BD1 but >100⯵M for BD2. The compound exhibited a broad spectrum of anti-proliferative activity against several human cancer and fibroblastic cell lines, which might be related to its capability of reducing the expression of c-Myc and collagen I. Furthermore, it could induce apoptosis in A375 cells. To the contrary, the selective BD2 inhibitor, RVX-208, did not indicate any of these activities. Our findings highlight that the function of BRD4-BD1 might be predominant in fibrosis and cancer. And it is rational to further develop novel selective BRD4-BD1 inhibitors.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Desenho de Fármacos , Fatores de Transcrição/antagonistas & inibidores , Sítios de Ligação , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Desenho Assistido por Computador , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Ligação de Hidrogênio , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
The dysfunction and mutual compensatory activation of RAF-MEK-ERK and PI3K-PDK1-AKT pathways have been demonstrated as the hallmarks in several primary and recurrent cancers. The strategy of concurrent blocking of these two pathways shows clinical merits on effective cancer therapy, such as combinatory treatments and dual-pathway inhibitors. Herein, we report a novel prototype of dual-pathway inhibitors by means of merging the core structural scaffolds of a MEK1 inhibitor and a PDK1 inhibitor. A library of 43 compounds that categorized into three series (Series I-III) was synthesized and tested for antitumor activity in lung cancer cells. The results from structure-activity relationship (SAR) analysis showed the following order of antitumor activity that 3-hydroxy-5-(phenylamino) indolone (Series III)â¯>â¯3-alkenyl-5-(phenylamino) indolone (Series I)â¯>â¯3-alkyl-5-(phenylamino) indolone (Series II). A lead compound 9za in Series III showed most potent antitumor activity with IC50 value of 1.8⯱â¯0.8⯵M in A549 cells. Moreover, antitumor mechanism study demonstrated that 9za exerted significant apoptotic effect, and cellular signal pathway analysis revealed the potent blockage of phosphorylation levels of ERK and AKT in RAF-MEK-ERK and PI3K-PDK1-AKT pathways, respectively. The results reported here provide robust experimental basis for the discovery and optimization of dual pathway agents for anti-lung cancer therapy.
Assuntos
Indóis/química , Indóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células A549 , Aminação , Compostos de Anilina/síntese química , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzodioxóis/síntese química , Benzodioxóis/química , Benzodioxóis/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Indóis/síntese química , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Quinases raf/metabolismoRESUMO
BACKGROUND/AIMS: Cyclosporine A (CsA) is an immunosuppressant drug that is used during organ transplants. However, its utility is limited by its nephrotoxic potential. This study aimed to investigate whether fluorofenidone (AKF-PD) could provide protection against CsA-induced nephrotoxicity. METHODS: Eighty-five male Sprague-Dawley rats were divided into 5 groups: drug solvent, CsA, CsA with AKF-PD (250, 500 mg/kg/day), and CsA with pirfenidone (PFD, 250 mg/kg/day). Tubulointerstitial injury index, extracellular matrix (ECM) deposition, expression of type I and IV collagen, transforming growth factor (TGF)-ß1, platelet-derived growth factor (PDGF), Fas ligand (FASL), cleaved-caspase-3, cleaved-poly(ADP-ribose) polymerase (PARP)-1, and the number of transferase-mediated nick end-labeling (TUNEL)-positive renal tubule cells were determined. In addition, levels of TGF-ß1, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of annexin V-positive cells were determined in rat proximal tubular epithelial cells (NRK-52E) treated with CsA (20 µmol/L), AKF-PD (400 µg/mL), PFD (400 µg/mL), and GW788388 (5 µmol/L). RESULTS: AKF-PD (250, 500 mg/kg/day) significantly reduced tubulointerstitial injury, ECM deposition, expression of type I and IV collagen, TGF-ß1, PDGF, FASL, cleaved-caspase-3, cleaved-PARP-1, and number of TUNEL-positive renal tubule cells in the CsA-treated kidneys. In addition, AKF-PD (400 µg/mL) significantly decreased TGF-ß1, FASL, cleaved-caspase-3, and PARP-1 expression in NRK-52E cells and further reduced the number of annexin V-positive cells. CONCLUSION: AKF-PD protect kidney from fibrosis and apoptosis in CsA-induced kidney injury.
Assuntos
Ciclosporina/toxicidade , Fibrose/prevenção & controle , Rim/lesões , Piridonas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Rim/patologia , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
A series of pyrazolo[3,4-b]pyridine derivatives were designed, synthesized, and evaluated for their activation activity toward adenosine 5'-monophosphate-activated protein kinase (AMPK). According to the enzyme activity, the pyrazole N-H exposure and para substitution on the diphenyl group were proved to be essential for the activation potency. Compound 17f showed equal activation compared with A-769662. In the molecular modeling study, compound 17f exhibited important hydrogen bond interaction with Lys29, Asp88, and Arg83. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays on the NRK-49F cell line showed that potent enzyme activators could effectively inhibit cell proliferation, especially for 17f (EC50 [AMPKα1γ1ß1] = 0.42 µM, efficacy = 79%; IC50 [NRK-49F cell line] = 0.78 µM). These results might provide new insights to explore novel AMPK activators.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Pirazóis/farmacologia , Piridinas/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Piridinas/síntese química , Piridinas/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90µM in NIH3T3 cell lines, t1/2 of 4.89±1.33h in male rats and LD50>2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Falência Renal Crônica/tratamento farmacológico , Piperazinas/farmacologia , Piridonas/farmacologia , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Relação Dose-Resposta a Droga , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Falência Renal Crônica/patologia , Masculino , Camundongos , Estrutura Molecular , Células NIH 3T3 , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/administração & dosagem , Piperazinas/química , Piridonas/administração & dosagem , Piridonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
NADPH oxidases (NOXs) are the key enzymes of redox signaling in vivo and also the main source of reactive oxygen species (ROS) in the body. ROS plays a role of double-edged sword. On the one hand, ROS, at the level of physiological amount, has the effect of immune defense and also acts as a second messenger involved in the regulation of cellular signaling pathways. On the other hand, excessive ROS can cause oxidative stress, leading to the disorder of cellular functions. Recently, studies showed that ROS plays an important role in acceleration of some pathological reactions such as inflammation, fibrosis and tumor formation. As a major source of ROS, NOX has become a popular target in treating oxidative stress, inflammation, fibrosis and tumor. Herein, the role of NOX in these pathological processes and the research progress of NOX inhibitors are reviewed.
Assuntos
NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Estresse Oxidativo , Animais , Fibrose/enzimologia , Humanos , Inflamação/enzimologia , Neoplasias/enzimologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Cyclin-dependent kinase-5(Cdk5) is a kind of Ser/Thr kinases in the signaling pathway, which regulates the neural development. The recent studies have confirmed that hyperactivation of Cdk5 is closely associated with the evolution, progression and apoptosis of tumors. The Cdk5 inhibitors have been extensively studied in the drug discovery against cancer. The structure features of these inhibitors and molecular mechanisms of their activities have provided clues for the drug development. In the second generation Cdk5 inhibitors, the ATP-binding pocket, a highly conserved site, has been targeted in the drug design in most cases. In addition, a growing number of peptides has been generated by targeting the protein/protein interfaces of Cdk5.
Assuntos
Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Neoplasias/tratamento farmacológico , HumanosRESUMO
p70 ribosomal protein S6 kinase (p70S6K), an important member of AGC family, is a kind of multifunctional Ser/Thr kinases, which plays an important role in mTOR signaling cascade. The p70 ribosomal protein S6 kinase is closely associated with diverse cellular processes such as protein synthesis, mRNA processing, glucose homeostasis, cell growth and apoptosis. Recent studies have highlighted the important role of S6K in cancer, which arose interests of scientific researchers for the design and discovery of anti-cancer agents. Herein, the mechanisms of S6K and available inhibitors are reviewed.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Quinases S6 Ribossômicas 70-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Antineoplásicos , Humanos , Transdução de Sinais , Serina-Treonina Quinases TORRESUMO
Currently, various antimitotic inhibitors applied in tumor therapy. However, these inhibitors exhibit targeted toxicity to some extent. As a motor protein, kinesin family member 18A (KIF18A) is crucial to spindle formation and is associated with tumors exhibiting ploidy-specific characteristics such as chromosomal aneuploidy, whole-genome doubling (WGD), and chromosomal instability (CIN). Differing from traditional antimitotic targets, KIF18A exhibits tumor-specific selectivity. The functional loss or attenuation of KIF18A results in vulnerability of tumor cells with ploidy-specific characteristics, with lesser effects on diploid cells. Research on inhibitors targeting KIF18A with ploidy-specific lethality holds significant importance. This review provides a brief overview of the regulatory mechanisms of the ploidy-specific lethality target KIF18A and the research advancements in its inhibitors, aiming to facilitate the development of KIF18A inhibitors.
RESUMO
NADPH oxidases (NOXs) are the sole enzyme in the human body that can directly produce reactive oxygen species. Recent studies have shown that NOXs is a very promising target for the treatment of diabetic nephropathy (DN). Here, a series of quinoline(quinolinone) derivatives have been designed based on pharmacophore strategy, synthesized and evaluated. Among them, 19d exhibits potent antiproliferative and NOXs inhibitory activities, and is worthy for further investigation.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , NADPH Oxidases , Quinolinas , Quinolonas , Humanos , NADPH Oxidases/metabolismo , NADPH Oxidases/antagonistas & inibidores , Quinolinas/química , Quinolinas/farmacologia , Quinolinas/síntese química , Quinolonas/química , Quinolonas/farmacologia , Quinolonas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.