RÉSUMÉ
The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.
Sujet(s)
Conception de médicament , Inflammasomes , Protéine-3 de la famille des NLR contenant un domaine pyrine , Sesquiterpènes , Protéine-3 de la famille des NLR contenant un domaine pyrine/antagonistes et inhibiteurs , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Humains , Inflammasomes/métabolisme , Inflammasomes/antagonistes et inhibiteurs , Animaux , Sesquiterpènes/pharmacologie , Sesquiterpènes/synthèse chimique , Sesquiterpènes/composition chimique , Souris , Relation structure-activité , Interleukine-1 bêta/métabolisme , Cellules THP-1 , Rectocolite hémorragique/traitement médicamenteux , Rectocolite hémorragique/métabolisme , Souris de lignée C57BLRÉSUMÉ
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulatory factor in the necroptosis signaling pathway, and is considered an attractive therapeutic target for treating multiple inflammatory diseases. Herein, we describe the design, synthesis, and structure-activity relationships of 4-amino-1,6-dihydro-7H-pyrrolo [2,3-d]pyridazin-7-one derivatives as RIPK1 inhibitors. Among them, 13c showed favorable RIPK1 kinase inhibition activity with an IC50 value of 59.8 nM, and high RIPK1 binding affinity compared with other regulatory kinases of necroptosis (RIPK1 Kd = 3.5 nM, RIPK3 Kd = 1700 nM, and MLKL Kd > 30,000 nM). 13c efficiently blocked TNFα-induced necroptosis in both human and murine cells (EC50 = 1.06-4.58 nM), and inhibited TSZ-induced phosphorylation of the RIPK1/RIPK3/MLKL pathway. In liver microsomal assay studies, the clearance rate and half-life of 13c were 18.40 mL/min/g and 75.33 min, respectively. 13c displayed acceptable pharmacokinetic characteristics, with oral bioavailability of 59.55%. In TNFα-induced systemic inflammatory response syndrome, pretreatment with 13c could effectively protect mice from loss of body temperature and death. Overall, these compounds are promising candidates for future optimization studies.
Sujet(s)
Protein kinases , Facteur de nécrose tumorale alpha , Souris , Humains , Animaux , Protein kinases/métabolisme , Facteur de nécrose tumorale alpha/pharmacologie , Facteur de nécrose tumorale alpha/métabolisme , Receptor-Interacting Protein Serine-Threonine Kinases/métabolisme , Phosphorylation , Thréonine/pharmacologie , Sérine/pharmacologie , ApoptoseRÉSUMÉ
Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients. Described herein are the obstacles that were encountered and the solutions that were found, which eventually led to the identification of compound 31t. This compound exhibited a remarkable combination of robust potency and exceptional selectivity along with favorable in vivo profiles as substantiated by pharmacokinetic studies in rats and pharmacodynamic assessments in H460, BT474, and A549 xenograft models.
Sujet(s)
Antinéoplasiques , Humains , Rats , Animaux , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/pharmacocinétique , Lignée cellulaire tumoraleRÉSUMÉ
ATM plays an important role in DNA damage response and is considered a potential target in cancer therapies. In this study, a goal-directed molecular generation approach based on ligand similarity and target specificity was applied to sample active molecules, and they were screened virtually to identify the theoretical lead compound 7a, which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability in vitro. Subsequent optimization was performed to improve the potency and selectivity toward ATM and attenuate the hepatic clearance in vitro, culminating in the identification of 10r with nanomolar ATM inhibition, excellent cellular sensitivity to radiation and chemotherapy drugs, and impressive pharmacokinetic profiles. Furthermore, 10r combined with irinotecan demonstrated a synergistic antitumor efficacy in SW620 xenograft models, suggesting that it could be a promising candidate drug combined with chemotherapy for the treatment of cancer.
Sujet(s)
Tumeurs , Quinoxalines , Humains , Objectifs , Dépistage précoce du cancer , Irinotécan/pharmacologie , Irinotécan/usage thérapeutique , Protéines mutées dans l'ataxie-télangiectasie/métabolismeRÉSUMÉ
Salt-inducible kinases (SIKs) play a crucial role in inflammation process, acting as molecular switches that regulate the transformation of M1/M2 macrophages. HG-9-91-01 is a SIKs inhibitor with potent inhibitory activity against SIKs in the nanomolar range. However, its poor drug-like properties, including a rapid elimination rate, low in vivo exposure and high plasma protein binding rate, have hindered further research and clinical application. To improve the drug-like properties of HG-9-91-01, a series of pyrimidine-5-carboxamide derivatives were designed and synthesized through a molecular hybridization strategy. The most promising compound 8h was obtained with favorable activity and selectivity on SIK1/2, excellent metabolic stability in human liver microsome, enhanced in vivo exposure and suitable plasma protein binding rate. Mechanism research showed that compound 8h significantly up-regulated the expression of anti-inflammatory cytokine IL-10 and reduced the expression of pro-inflammatory cytokine IL-12 in bone marrow-derived macrophages. Furthermore, it significantly elevated expression of cAMP response element-binding protein (CREB) target genes IL-10, c-FOS and Nurr77. Compound 8h also induced the translocation of CREB-regulated transcriptional coactivator 3 (CRTC3) and elevated the expression of LIGHT, SPHK1 and Arginase 1. Additionally, compound 8h demonstrated excellent anti-inflammatory effects in a DSS-induced colitis model. Generally, this research indicated that compound 8h has the potential to be developed as an anti-inflammatory drug candidate.
Sujet(s)
Maladies inflammatoires intestinales , Interleukine-10 , Humains , Cytokines/métabolisme , Maladies inflammatoires intestinales/traitement médicamenteux , Protein-Serine-Threonine Kinases , Pyrimidines/composition chimiqueRÉSUMÉ
Background: Triple-negative breast cancer (TNBC) is proposed at the beginning of this century, which is still the most challenging breast cancer subtype due to its aggressive behavior, including early relapse, metastatic spread, and poor survival. This study uses machine learning methods to explore the current research status and deficiencies from a macro perspective on TNBC publications. Methods: PubMed publications under "triple-negative breast cancer" were searched and downloaded between January 2005 and 2022. R and Python extracted MeSH terms, geographic information, and other abstracts from metadata. The Latent Dirichlet Allocation (LDA) algorithm was applied to identify specific research topics. The Louvain algorithm established a topic network, identifying the topic's relationship. Results: A total of 16,826 publications were identified, with an average annual growth rate of 74.7%. Ninety-eight countries and regions in the world participated in TNBC research. Molecular pathogenesis and medication are most studied in TNBC research. The publications mainly focused on three aspects: Therapeutic target research, Prognostic research, and Mechanism research. The algorithm and citation suggested that TNBC research is based on technology that advances TNBC subtyping, new drug development, and clinical trials. Conclusion: This study quantitatively analyzes the current status of TNBC research from a macro perspective and will aid in redirecting basic and clinical research toward a better outcome for TNBC. Therapeutic target research and Nanoparticle research are the present research focus. There may be a lack of research on TNBC from a patient perspective, health economics, and end-of-life care perspectives. The research direction of TNBC may require the intervention of new technologies.
RÉSUMÉ
Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/ß signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.
Sujet(s)
Kinase Janus-2 , Syndromes myéloprolifératifs , Humains , Protéines nucléaires , Facteur de transcription NF-kappa B , Facteurs de transcription/métabolisme , Syndromes myéloprolifératifs/traitement médicamenteux , Protéines du cycle cellulaireRÉSUMÉ
Nowadays, PI3Kδ-γ dual inhibitors have been approved for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ and PI3Kγ represents a unique therapeutic opportunity and may confer greater benefits than either isoform inhibition alone in the management of hematological malignancies. However, currently available dual inhibitors of PI3Kδ-γ compromise in at least one of several essential properties in terms of potency, selectivity, and pharmacokinetic (PK) profiles. Hence, the main challenge of our optimization campaign was to identify an oral available PI3Kδ-γ dual inhibitor with an optimum balance of potency, selectivity, and PK profiles. The medicinal chemistry efforts culminated in the discovery of compound 58, which exhibited strong potency and high selectivity along with excellent in vivo profiles as demonstrated through PK studies in rats and through pharmacodynamic studies in an SUDHL-6 xenograft model. All the results suggest that compound 58 may be a promising candidate for the treatment of B-cell malignancies.
Sujet(s)
Tumeurs , Inhibiteurs de protéines kinases , Animaux , Lymphocytes B , Phosphatidylinositol 3-kinases de classe I , Humains , Inhibiteurs des phosphoinositide-3 kinases , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , RatsRÉSUMÉ
Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of a series of RIPK2 inhibitors derived from an FLT3 inhibitor, CHMFL-FLT3-165. Compound 10w was identified to possess an IC50 value of 0.6 nM for RIPK2 and greater than 50,000-fold selectivity over its family homologous kinase RIPK1 (IC50 > 30 µM). It exhibited high kinase selectivity and inhibited RIPK2 to prevent NOD-induced cytokine production following muramyl dipeptide (MDP) stimulation. In an acute colitis model, compound 10w exerted better therapeutic effects than the JAK inhibitor filgotinib and the RIPK2 inhibitor WEHI-345. These robust results of in vitro and in vivo pharmacodynamic experiments demonstrate that RIPK2 as a therapeutic target shows potential abilities for the treatment of inflammatory bowel diseases.
Sujet(s)
Maladies inflammatoires intestinales , Receptor-Interacting Protein Serine-Threonine Kinase 2 , Acétylmuramyl alanyl isoglutamine/métabolisme , Humains , Maladies inflammatoires intestinales/traitement médicamenteux , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Receptor-Interacting Protein Serine-Threonine Kinases , Sérine , ThréonineRÉSUMÉ
FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.
Sujet(s)
Antinéoplasiques , Leucémie aigüe myéloïde , Lignée cellulaire tumorale , Prolifération cellulaire , Kinase-4 cycline-dépendante , Humains , Leucémie aigüe myéloïde/traitement médicamenteux , Inhibiteurs de protéines kinases , Pyridines , Relation structure-activité , Tyrosine kinase-3 de type fmsRÉSUMÉ
Clinical FLT3 mutations caused poor therapeutic benefits toward the present FLT3 inhibitors, and degradation of the FLT3 mutant protein may be a promising alternative approach to protect against acute myeloid leukemia (AML). Herein, we report the discovery of small molecule FLT3 degraders based on the proteolysis targeting chimera (PROTAC). FLT3 degraders were designed, synthesized, and evaluated for FLT3 degradation. Promising PF15 significantly inhibited the proliferation of FLT3-ITD-positive cells, induced FLT3 degradation and downregulated the phosphorylation of FLT3 and STAT5. An in vivo xenograft model and survival period evaluation verified the efficacy of PROTAC. These findings laid a robust foundation for FLT3-PROTAC molecules as an effective strategy for treating AML.
Sujet(s)
Antinéoplasiques/pharmacologie , Lénalidomide/pharmacologie , Inhibiteurs de protéines kinases/pharmacologie , Bibliothèques de petites molécules/pharmacologie , Tyrosine kinase-3 de type fms/antagonistes et inhibiteurs , Animaux , Antinéoplasiques/synthèse chimique , Antinéoplasiques/composition chimique , Lignée cellulaire tumorale , Prolifération cellulaire/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Tests de criblage d'agents antitumoraux , Femelle , Humains , Lénalidomide/synthèse chimique , Lénalidomide/composition chimique , Souris , Souris de lignée NOD , Souris SCID , Structure moléculaire , Mutation , Tumeurs expérimentales/traitement médicamenteux , Tumeurs expérimentales/métabolisme , Tumeurs expérimentales/anatomopathologie , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Protéolyse/effets des médicaments et des substances chimiques , Bibliothèques de petites molécules/synthèse chimique , Bibliothèques de petites molécules/composition chimique , Relation structure-activité , Tyrosine kinase-3 de type fms/génétique , Tyrosine kinase-3 de type fms/métabolismeRÉSUMÉ
Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl". Further optimization around the "3rd blade" of the propeller led to identification of a series of potent and selective PI3Kδ inhibitors. Among them, compound 50 afforded an optimum balance of PK profiles and potency. Oral administration of 50 attenuated the arthritis severity in a dose-dependent manner in a collagen-induced arthritis model without obvious toxicity. Furthermore, 50 demonstrated excellent pharmacokinetic properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Arthrite expérimentale/traitement médicamenteux , Phosphatidylinositol 3-kinases de classe I/antagonistes et inhibiteurs , Inflammation/traitement médicamenteux , Inhibiteurs de protéines kinases/pharmacologie , Quinazolinones/pharmacologie , Animaux , Anti-inflammatoires non stéroïdiens/synthèse chimique , Anti-inflammatoires non stéroïdiens/composition chimique , Arthrite expérimentale/induit chimiquement , Phosphatidylinositol 3-kinases de classe I/métabolisme , Relation dose-effet des médicaments , Découverte de médicament , Humains , Inflammation/induit chimiquement , Souris , Souris de lignée DBA , Microsomes du foie/composition chimique , Microsomes du foie/métabolisme , Structure moléculaire , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/composition chimique , Quinazolinones/administration et posologie , Quinazolinones/composition chimique , Relation structure-activitéRÉSUMÉ
TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1H-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound 14l exhibited acceptable TYK2 inhibition with an IC50 value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood. In liver microsomal assay studies, the clearance rate and half-life of 14l were 11.4 mL/min/g and 121.6 min, respectively. Furthermore, in a dextran sulfate sodium colitis model, 14l reduced the production of pro-inflammatory cytokines IL-6 and TNF-α and improved the inflammation symptoms of mucosal infiltration, thickening, and edema. Taken together, 14l was a selective TYK2 inhibitor and could be used to treat immune diseases deserving further investigation.
Sujet(s)
Agents gastro-intestinaux/usage thérapeutique , Maladies inflammatoires intestinales/traitement médicamenteux , Inhibiteurs de protéines kinases/usage thérapeutique , Pyrazoles/usage thérapeutique , Pyrimidines/usage thérapeutique , TYK2 Kinase/antagonistes et inhibiteurs , Animaux , Lignée cellulaire tumorale , Côlon/anatomopathologie , Stabilité de médicament , Agents gastro-intestinaux/synthèse chimique , Agents gastro-intestinaux/métabolisme , Humains , Maladies inflammatoires intestinales/anatomopathologie , Mâle , Microsomes du foie/métabolisme , Simulation de docking moléculaire , Structure moléculaire , Liaison aux protéines , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/métabolisme , Pyrazoles/synthèse chimique , Pyrazoles/métabolisme , Pyrimidines/synthèse chimique , Pyrimidines/métabolisme , Rat Sprague-Dawley , Relation structure-activité , TYK2 Kinase/métabolismeRÉSUMÉ
Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC50 values of 0.63-0.93 µM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation.
Sujet(s)
Antinéoplasiques d'origine végétale/composition chimique , Autophagie/effets des médicaments et des substances chimiques , Dérivés du biphényle/composition chimique , Carcinome pulmonaire non à petites cellules/traitement médicamenteux , Lignanes/composition chimique , Tumeurs du poumon/traitement médicamenteux , Magnolia/composition chimique , Extraits de plantes/composition chimique , Animaux , Antinéoplasiques d'origine végétale/pharmacologie , Apoptose/effets des médicaments et des substances chimiques , Dérivés du biphényle/pharmacologie , Points de contrôle du cycle cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Tests de criblage d'agents antitumoraux , Femelle , Humains , Lignanes/pharmacologie , Souris de lignée BALB C , Solubilité , Relation structure-activitéRÉSUMÉ
Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening and interstitial lung disease with the median survival of only 3-5 years. However, due to the unclear etiology and problems in accurate diagnosis, up to now only two drugs were approved by FDA for the treatment of IPF and their outcome responses are limited. Numerous studies have shown that TGF-ß is the most important cytokine in the development of pulmonary fibrosis and plays a role through its downstream signaling molecule TGF-binding receptor Smads protein. In this paper, compounds bearing 2(1H)-quinolone scaffold were designed and their anti-fibrosis effects were evaluated. Of these compounds, 20f was identified as the most active one and could inhibit TGF-ß-induced collagen deposition of NRK-49F cells and mouse fibroblasts migration with comparable activity and lower cytotoxicity than nintedanib in vitro. Further mechanism studies indicated that 20f reduced the expression of fibrogenic phenotypic protein α-SMA and collagen â by inhibiting the TGF-ß/Smad dependent pathways and ERK1/2 and p38 pathways. Moreover, compared with the nintedanib, 20f (100 mg/kg/day, p.o) more effectively alleviated collagen deposition in lung tissue and delayed the destruction of lung tissue structure both in bleomycin-induced prevention and treatment mice pulmonary fibrosis models. The immunohistochemical experiments further showed that 20f could block the expression level of phosphorylated Smad3 in the lung tissue cells, which resulted in its anti-fibrosis effects in vivo. In addition, 20f demonstrated good bioavailability (F = 41.55% vs 12%, compare with nintedanib) and an appropriate elimination half-life (T1/2 = 3.5 h), suggesting that 20f may be a potential drug candidate for the treatment of pulmonary fibrosis.
Sujet(s)
Fibrose pulmonaire idiopathique/traitement médicamenteux , Quinolinone/usage thérapeutique , Transduction du signal/effets des médicaments et des substances chimiques , Actines/métabolisme , Animaux , Bléomycine , Lignée cellulaire , Mouvement cellulaire/effets des médicaments et des substances chimiques , Collagène de type I/métabolisme , Conception de médicament , Fibrose pulmonaire idiopathique/induit chimiquement , Poumon/anatomopathologie , Mâle , Souris de lignée C57BL , Structure moléculaire , Quinolinone/synthèse chimique , Quinolinone/pharmacocinétique , Quinolinone/toxicité , Rat Sprague-Dawley , Protéine Smad2/métabolisme , Protéine Smad-3/métabolisme , Relation structure-activité , Facteur de croissance transformant bêta/métabolismeRÉSUMÉ
Idiopathic pulmonary fibrosis, characterized by excess accumulation of extracellular matrix, involved in many chronic diseases or injuries, threatens human health greatly. We have reported a series of compounds bearing coumarin scaffold which potently inhibited TGF-ß-induced total collagen accumulation in NRK-49F cell line and migration of macrophages. Compound 9d also suppressed the TGF-ß-induced protein expression of COL1A1, α-SMA, and p-Smad3 in vitro. Meanwhile, 9d at a dose of 100â¯mg/kg/day through oral administrations for 4 weeks effectively alleviated infiltration of inflammatory cells in lung tissue and fibrotic degree in bleomycin-induced pulmonary fibrosis model, which may related to its inhibition of TGF-ß/Smad3 pathway and anti-inflammation efficacy. In addition, 9d demonstrated decent bioavailability (Fâ¯=â¯39.88%) and suitable eliminated half-life time (T1/2â¯=â¯13.09â¯h), suggesting that 9d could be a potential drug candidate for the treatment of fibrotic diseases.
Sujet(s)
Coumarines/usage thérapeutique , Découverte de médicament , Fibrose pulmonaire/traitement médicamenteux , Animaux , Bléomycine , Mouvement cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Coumarines/synthèse chimique , Coumarines/composition chimique , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Mâle , Souris , Souris de lignée C57BL , Structure moléculaire , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Cellules RAW 264.7 , Relation structure-activitéRÉSUMÉ
BACKGROUND: The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification of these genes would be of considerable interest. RESULTS: To begin to address this issue, microarray technology was employed to elucidate in a de novo fashion the global role of RIP140 in RA target gene regulation of embryonal carcinoma. Subclasses of genes were affected by RIP140 in distinct manners.Interestingly, approximately half of the RA-dependent genes were unaffected by RIP140. Hence, RIP140 appears to discriminate between different classes of RA target genes. In general, RIP140-dependent gene expression was consistent with RIP140 functioning to limit RA signaling and tumor cell differentiation. Few if any genes were regulated in a manner to support a role for RIP140 in "active repression". We also demonstrated that RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA. CONCLUSION: Together the data demonstrates that RIP140 has profound effects on RA-mediated gene expression in this cancer stem cell model. The RIP140-dependent RA target genes identified here may be particularly important in mediating RA-induced tumor cell differentiation and the findings suggest that RIP140 may be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy. We discuss these data in the context of proposed models of RIP140-mediated repression.
Sujet(s)
Protéines adaptatrices de la transduction du signal/physiologie , Carcinome embryonnaire/anatomopathologie , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Cellules souches tumorales/effets des médicaments et des substances chimiques , Protéines nucléaires/physiologie , Cellules souches pluripotentes/effets des médicaments et des substances chimiques , Trétinoïne/pharmacologie , Différenciation cellulaire/effets des médicaments et des substances chimiques , Différenciation cellulaire/génétique , Cellules souches de carcinome embryonnaire , Rétrocontrôle physiologique , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes tumoraux/physiologie , Humains , Protéines tumorales/biosynthèse , Protéines tumorales/génétique , Cellules souches tumorales/métabolisme , Protéine-1 interagissant avec le récepteur nucléaire , Séquençage par oligonucléotides en batterie , Cellules souches pluripotentes/métabolisme , Interférence par ARN , Petit ARN interférent/pharmacologie , Récepteurs à l'acide rétinoïque/biosynthèse , Récepteurs à l'acide rétinoïque/génétique , Transduction du signal/effets des médicaments et des substances chimiques , Transduction du signal/physiologie , Transcription génétiqueRÉSUMÉ
The receptor interacting protein 140 (RIP140) belongs to a unique subclass of nuclear receptor coregulators with the ability to bind and repress the action of a number of agonist-bound hormone receptors. We have previously demonstrated that all-trans-retinoic acid (RA) induction of RIP140 constitutes a rate-limiting step in the regulation of retinoid receptor signaling. Here we demonstrate that RIP140 is also a limiting regulator of estrogen receptor signaling. Overexpression of RIP140 dose dependently inhibits estrogen-dependent reporter activity in human breast cancer cells. Furthermore, small interfering RNA to RIP140 enhances estrogen-dependent signaling. Our previous studies indicate that RIP140 is a direct target of RA. We report here that RA can abrogate estrogen-mediated cell cycle re-entry. In addition, RA treatment of estrogen-dependent breast cancer cells opposes estrogen receptor-dependent reporter activity, implying that a proportion of RA effects are anti-estrogenic. We provide evidence for a role for RIP140 in mediating anti-estrogenic effects of RA. RIP140 small interfering RNA blocks RA-mediated repression of estrogen receptor activity and provides a growth advantage to estrogen-dependent cells. Together these data implicate a regulatory role for RIP140 in mediating anti-estrogenic effects of RA in estrogen-dependent breast cancer cells and suggest that acute regulation of coregulator expression may be a general mechanism to integrate diverse hormone signals.