RESUMEN
There is a lack of effective treatments to overcome resistance to EGFR-TKIs in EGFR mutant tumors. A deeper understanding of resistance mechanisms can provide insights into reducing or eliminating resistance, and can potentially deliver targeted treatment measures to overcome resistance. Here, we identified that the dynamic changes of the tumor immune environment were important extrinsic factors driving tumor resistance to EGFR-TKIs in EGFR mutant cell lines and syngeneic tumor-bearing mice. Our results demonstrate that the acquired resistance to EGFR-TKIs is accompanied by aberrant expression of PD-L2, leading a dynamic shift from an initially favorable tumor immune environment to an immunosuppressive phenotype. PD-L2 expression significantly affected EGFR mutant cell apoptosis that depended on the proportion and function of CD8+ T cells in the tumor immune environment. Combined with single-cell sequencing and experimental results, we demonstrated that PD-L2 specifically inhibited the proliferation of CD8+ T cells and the secretion of granzyme B and perforin, leading to reduced apoptosis mediated by CD8+ T cells and enhanced immune escape of tumor cells, which drives EGFR-TKIs resistance. Importantly, we have identified a potent natural small-molecule inhibitor of PD-L2, zinc undecylenate. In vitro, it selectively and potently blocks the PD-L2/PD-1 interaction. In vivo, it abolishes the suppressive effect of the PD-L2-overexpressing tumor immune microenvironment by blocking PD-L2/PD-1 signaling. Moreover, the combination of zinc undecylenate and EGFR-TKIs can synergistically reverse tumor resistance, which is dependent on CD8+ T cells mediating apoptosis. Our study uncovers the PD-L2/PD-1 signaling pathway as a driving factor to mediate EGFR-TKIs resistance, and identifies a new naturally-derived agent to reverse EGFR-TKIs resistance.
Asunto(s)
Resistencia a Antineoplásicos , Receptores ErbB , Proteína 2 Ligando de Muerte Celular Programada 1 , Inhibidores de Proteínas Quinasas , Microambiente Tumoral , Animales , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Humanos , Microambiente Tumoral/efectos de los fármacos , Ratones , Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Línea Celular Tumoral , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Apoptosis/efectos de los fármacos , Femenino , Terapia Molecular DirigidaRESUMEN
Epilepsy is a progressive neurodegenerative disease highlighted by recurrent seizures, neuroinflammation, and the loss of neurons. Microglial dysfunction is commonly found in epileptic foci and contributes to neuroinflammation in the initiation and progression of epilepsy. Glycoprotein non-metastatic melanoma protein B (GPNMB), a transmembrane glycoprotein, has been involved in the microglial activation and neuroinflammation response. The present study investigated the functional significance of GPNMB in epilepsy. A proven model of epilepsy was established by intraperitoneal injection of pilocarpine to male Sprague Dawley rats. Lentivirus vectors carrying GPNMB or GPNMB short hairpin RNA (shGPNMB) were injected into the hippocampus to induce overexpression or knockdown of GPNMB. GPNMB expression was significantly upregulated and overexpression of GPNMB in the hippocampus reduced seizure activity and neuronal loss after status epilepticus (SE). We here focused on the effects of GPNMB deficiency on neuronal injury and microglia polarization 28 days after SE. GPNMB knockdown accelerated neuronal damage in the hippocampus, evidenced by increased neuron loss and neuronal cell apoptosis. Following GPNMB knockdown, M1 polarization (iNOS) and secretion of pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α were increased, and M2 polarization (Arg1) and secretion of anti-inflammatory cytokines IL-4, IL-10, and TGF-ß were decreased. BV2 cells were used to further confirm the regulatory role of GPNMB in modulating phenotypic transformations and inflammatory cytokine expressions in microglia. In conclusion, these results indicated that GPNMB suppressed epilepsy through repression of hippocampal neuroinflammation, suggesting that GPNMB might be considered the potential neurotherapeutic target for epilepsy management and play a protective role against epilepsy by modulating the polarization of microglia.
Asunto(s)
Epilepsia , Glicoproteínas de Membrana , Microglía , Enfermedades Neuroinflamatorias , Neuronas , Pilocarpina , Ratas Sprague-Dawley , Animales , Microglía/metabolismo , Masculino , Pilocarpina/toxicidad , Glicoproteínas de Membrana/metabolismo , Ratas , Epilepsia/metabolismo , Epilepsia/inducido químicamente , Epilepsia/patología , Neuronas/metabolismo , Neuronas/patología , Enfermedades Neuroinflamatorias/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Citocinas/metabolismoRESUMEN
Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50â¯=â¯0.32â¯nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50â¯=â¯1.20â¯nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50â¯=â¯0.03â¯nM; EZH2 Y641N, IC50â¯=â¯0.08â¯nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50â¯=â¯0.37â¯nM; EZH2 Y641N, IC50â¯=â¯0.85â¯nM). Furthermore, compound N40 (IC50â¯=â¯3.52⯱â¯1.23â¯nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50â¯=â¯35.01⯱â¯1.28â¯nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2â¯=â¯177.69â¯min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2â¯=â¯7.97â¯min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.
Asunto(s)
Antineoplásicos , Benzamidas , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2 , Piridonas , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Humanos , Relación Estructura-Actividad , Benzamidas/química , Benzamidas/farmacología , Benzamidas/síntesis química , Piridonas/farmacología , Piridonas/química , Piridonas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patología , Relación Dosis-Respuesta a Droga , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Descubrimiento de Drogas , Bencimidazoles/química , Bencimidazoles/farmacología , Bencimidazoles/síntesis químicaRESUMEN
Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.
Asunto(s)
Antígeno B7-H1 , Neoplasias , Humanos , Animales , Ratones , NAD , Neoplasias/patología , Proliferación Celular , Apoptosis , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Gout is characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals around joints. Despite the availability of several drugs on the market, its treatment remains challenging owing to the notable side effects, such as hepatorenal toxicity and cardiovascular complications, that are associated with most existing agents. This perspective aims to summarize the current research progress in the development of antigout agents, particularly focusing on xanthine oxidase (XO) and urate anion transporter 1 (URAT1) inhibitors from a medicinal chemistry viewpoint and their preliminary structure-activity relationships (SARs). This perspective provides valuable insights and theoretical guidance to medicinal chemists for the discovery of antigout agents with novel chemical structures, better efficiency, and lower toxicity.
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Gota , Hiperuricemia , Humanos , Ácido Úrico/química , Ácido Úrico/uso terapéutico , Gota/tratamiento farmacológico , Hiperuricemia/tratamiento farmacológico , Supresores de la Gota/farmacología , Supresores de la Gota/uso terapéutico , Xantina OxidasaRESUMEN
We present a dual-layer hafnium dioxide (HfO2) grating capable of full-color modulation in the visible spectrum by leveraging the magnetic dipole resonance induced by the lower-layer HfO2 grating, while the upper-layer HfO2 grating serves as a refractive index matching layer to effectively suppress high-order Mie resonances at shorter wavelengths. The HfO2/HfO2 grating exhibits a significantly larger distribution area in the CIE 1931 chromaticity diagram compared to the HfO2 grating. Furthermore, the structural color saturation closely approximates that of monochromatic light. Under varying background refractive index environments, this structure consistently exhibits high-quality structural color. However, the hue of the structural color undergoes alterations. When the polarization angle is below 20°, the saturation of the acquired structural color remains remarkably consistent. However, exceeding 20° results in a significant degradation in the quality of the structural color. This study demonstrates the promising potential for diverse applications, encompassing fields such as imaging and displays.
RESUMEN
A series of pyrido[3,2-d]pyrimidine-containing 4-arylindolines were identified as potent inhibitors of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction by structural optimization of a 4-arylindoline precursor reported previously. Among them, compound N11 was the most promising inhibitor, showing an IC50 value of 6.3 nM against the PD-1/PD-L1 interaction at the biochemical level. In in vitro T-cell tumor co-culture models, N11 significantly promoted T-cell proliferation, activation, and infiltration into tumor spheres, demonstrating that it possessed excellent immunomodulatory activity. In addition, N11 exhibited favorable in vivo antitumor activity in an LLC/PD-L1 tumor-bearing mouse model. Flow cytometry analysis verified that the in vivo antitumor efficacy of N11 was dependent on the activation of the immune microenvironment. These findings suggest that N11 can serve as a new starting point for the future development of small-molecule antitumor immunomodulators targeting the PD-1/PD-L1 axis.
Asunto(s)
Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Animales , Ratones , Apoptosis , Inmunoterapia , Ligandos , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Indoles/química , Indoles/farmacologíaRESUMEN
Polo like kinase 1 (PLK1) is a serine/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (13a-13v and 21g-21l) possessing oxadiazoles moiety as potent inhibitors of PLK1. Compound 21g exhibited improved PLK1 inhibitory capability with an IC50 value of 0.45 nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC50 = 8.64 nM, HCT-116 IC50 = 26.0 nM, MDA-MB-231 IC50 = 14.8 nM and MV4-11 IC50 = 47.4 nM) with better pharmacokinetic characteristics than BI2536 in mice (AUC0-t = 11 227 ng h mL-1vs 556 ng h mL-1). Moreover, 21g exhibited moderate liver microsomal stability and excellent pharmacokinetic profile (AUC0-t = 11227 ng h mL-1, oral bioavailability of 77.4%) in Balb/c mice, acceptable PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the acute toxicity assay (20 mg/kg). Further investigation showed that 21 g could arrest HCT-116 cells in G2 phase and induce apoptosis in a dose-dependent manner. These results indicate that 21g is a promising PLK1 inhibitor.
Asunto(s)
Antineoplásicos , Ratones , Animales , Proliferación Celular , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas , Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinasas , Línea Celular Tumoral , ApoptosisRESUMEN
The elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Herein, we reported the discovery of a series of benzamide derivatives containing urea moiety as sEH inhibitors. Intensive structural modifications led to the identification of compound A34 as a potent sEH inhibitor with good physicochemical properties. Molecular docking revealed an additional hydrogen-bonding interaction between the unique amide scaffold and Phe497, contributing to sEH inhibition potency enhancement. Compound A34 exhibited outstanding inhibitory activity against human sEH, with an IC50 value of 0.04 ± 0.01 nM and a Ki value of 0.2 ± 0.1 nM. It also showed moderate systemic drug exposure and oral bioavailability in vivo metabolism studies. In carrageenan-induced inflammatory pain rat model, compound A34 exhibited a better therapeutic effect compared to t-AUCB and Celecoxib. Metabolism studies in vivo together with an inflammatory pain evaluation suggest that A34 may be a viable lead compound for the development of highly potent sEH inhibitors.
Asunto(s)
Inhibidores Enzimáticos , Epóxido Hidrolasas , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Simulación del Acoplamiento Molecular , Dolor , Ratas , Solubilidad , Urea/farmacologíaRESUMEN
With the great success of anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) monoclonal antibodies in clinical applications, blocking the PD-1/PD-L1 pathway has become the most compelling strategy in the field of tumor immunotherapy. In this study, a novel series of 4-phenylindolines containing a (5-cyanopyridin-3-yl)methoxy moiety were developed, and their structure-activity relationships were preliminarily discussed. Among them, compounds M17 and M23 exhibited the most potent ability to disrupt the PD-1/PD-L1 interaction, demonstrating IC50 values of 60.1 nM and 53.2 nM, respectively. The binding mode of M23 was further explored by molecular docking analysis with dimeric PD-L1. Therefore, M17 and M23 are promising lead compounds for developing potent inhibitors of the PD-1/PD-L1 axis.
Asunto(s)
Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , Antígeno B7-H1/química , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Receptor de Muerte Celular Programada 1/química , Relación Estructura-ActividadRESUMEN
Through specific structural modification of a 4-phenylindoline precursor, new 4-arylindolines containing a thiazole moiety were developed and found to be promising modulators of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis. Compound A30 exhibited outstanding biochemical activity, with an IC50 of 11.2 nM in a homogeneous time-resolved fluorescence assay. In the cell-based assay, A30 significantly promoted IFN-γ secretion and rescued T-cell proliferation, which were inhibited by PD-1 activation. Furthermore, A30 showed favorable in vivo antitumor activity in a mouse 4T1 breast carcinoma model. Moreover, in mouse CT26 colon carcinoma models, A30 potently suppressed the growth of CT26/PD-L1 tumor but did not obviously affect the growth of CT26/vector tumor. The results of flow cytometry analysis indicated that A30 inhibited tumor growth by activating the immune microenvironment. We concluded that A30 is a new starting point for further development of PD-1/PD-L1 interaction inhibitors as antitumor agents.
Asunto(s)
Antineoplásicos/química , Antígeno B7-H1/metabolismo , Indoles/química , Receptor de Muerte Celular Programada 1/metabolismo , Tiazoles/química , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Indoles/metabolismo , Indoles/farmacología , Indoles/uso terapéutico , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Mapas de Interacción de Proteínas/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The development of immune checkpoint inhibitors has become a research hotspot in cancer immunotherapy in recent years. Anti-PD-1/PD-L1 monoclonal antibodies (mAbs), such as pembrolizumab and nivolumab have been approved for treating different types of cancer. Many peptides, peptidomimetics and non-peptide small-molecule inhibitors targeting the PD-1/PD-L1 axis have been published so far. In comparison with mAbs, small-molecule inhibitors have the potential to overcome inherent shortcomings of mAbs, such as poor oral bioavailability, low tumor penetration, and high manufacturing costs. In this article, we mainly review non-peptide small-molecule inhibitors of the PD-1/PD-L1 interaction, their cocrystal structures, docking studies, and biological activities are also included to guide future study. In addition, we propose several strategies for designing more effective small-molecule modulators of the PD-1/PD-L1 pathway.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Desarrollo de Medicamentos , Inhibidores de Puntos de Control Inmunológico/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Antígeno B7-H1/química , Humanos , Inhibidores de Puntos de Control Inmunológico/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptor de Muerte Celular Programada 1/química , Unión Proteica/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC50 value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a "prodrug". In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Benzotiazoles/farmacología , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzotiazoles/síntesis química , Benzotiazoles/química , Carragenina , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/metabolismo , Células Hep G2 , Humanos , Inflamación/inducido químicamente , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Herein, with the help of computer-aided drug design (CADD), we describe the structure-based rational drug design, structure-activity relationships, and synthesis of a series of 2-aminopyrimidine derivatives that inhibit both JAK2 and FLT3 kinases. These screening cascades revealed that compound 14l demonstrated the most inhibitory activity with IC50 values of 1.8 and 0.68 nM against JAK2 and FLT3 respectively. 14l also showed potent anti-proliferative activities against HEL (IC50 = 0.84 µM) and Molm-13 (IC50 = 0.019 µM) cell lines, but relatively weak cytotoxicity against K562 and PC-3 cell lines, which proved that it might have high target specificity. In vitro metabolism assay, 14l exhibited moderate stability in RLM (Rat Liver Microsomes) with a half-life time of 31 min. In the cellular context of Molm-13, 14l induced cell cycle arrest in G1/S phase and enhanced apoptosis in a dose-dependent manner. These results indicate that 14l is a promising dual JAK2/FLT3 inhibitor and worthy of further development.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Janus Quinasa 2/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Janus Quinasa 2/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC50 values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Histona Desacetilasa 1/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Pruebas de Enzimas , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/metabolismo , Compuestos de Fenilurea/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Recently, PI3K and mTOR have been regarded as promising targets for cancer treatment. Herein, we designed and synthesized four series of novel thieno[3,2-d]pyrimidine derivatives that containing aroyl hydrazone or aryl hydrazide moieties. These derivatives act as PI3K/mTOR dual inhibitors, suggesting that they can be used as cancer therapeutic agents. All compounds were tested for anti-proliferative activity against four cancer cell lines. The structure-activity relationship (SAR) studies were conducted by varying the moieties at the C-6 and C-2 positions of the thieno[3,2-d]pyrimidine core. It indicated that aryl hydrazide at C-6 position and 2-aminopyrimidine at C-2 position are optimal fragments. Compound 18b showed the most potent in vitro activity (PI3Kα IC50 = 0.46 nM, mTOR IC50 = 12 nM), as well as good inhibition against PC-3 (human prostate cancer), HCT-116 (human colorectal cancer), A549 (human lung adenocarcinoma) and MDA-MB-231 (human breast cancer) cell lines. Furthermore, Annexin-V and propidium iodide (PI) double staining confirmed that 18b induces apoptosis in cytotoxic HCT-116 cells. Moreover, the influence of 18b on cell cycle distribution was assessed on the HCT-116 cell line, and a cell cycle arrest was observed at the G1/S phases.
Asunto(s)
Antineoplásicos/farmacología , Hidrazinas/farmacología , Hidrazonas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Hidrazinas/química , Hidrazonas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TOR/metabolismo , Células Tumorales CultivadasRESUMEN
Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC50 of 18.49 nM and remarkable inhibitory activity against c-Met with an IC50 of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC50 values of 0.22 µM, 1.59 µM and 0.22 µM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
Asunto(s)
Histona Desacetilasa 1/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación por Computador , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Structural modifications of compound 2, an angiokinase inhibitor reported by our group were performed, which led to the discovery of methyl (Z)-3-(((4-(2-methyl-5-((4-methylpiperazin-1-yl)methyl)-1H-pyrrol-1-yl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (7h). Compound 7h exhibited excellent inhibitory activity against angiokinases including VEGFR-1/2/3, PDGFRα/ß, and FGFR-1, as well as LYN and c-KIT kinases. At the cellular level, compound 7h significantly attenuated phosphorylation of AKT and ERK proteins, potently inhibited colony formation of HT-29, MKN74, and HepG2 cancer cells, and induced cell apoptosis. Upon incubation with human liver microsome, 7h exhibited comparable metabolic stability to nintedanib. Compound 7h has emerged as a promising lead compound for future drug design.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Oxindoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirroles/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones , Ratones Desnudos , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxindoles/síntesis química , Oxindoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Inhibiting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is an attractive strategy for tumor immunotherapy. Here, a novel series of indoline-containing compounds were developed, among which, A13 was identified as the most promising PD-1/PD-L1 pathway inhibitor. At the biochemical level, A13 demonstrated strong inhibition of the PD-1/PD-L1 interaction, with an IC50 of 132.8â¯nM. Notably, it exhibited outstanding immunoregulatory activity, and significantly elevated interferon-γ secretion in a Hep3B/OS-8/hPD-L1 and CD3 T cell co-culture model, without significant toxic effect. Therefore, A13 could be employed as a suitable lead compound for further design of non-peptide inhibitors targeting the PD-1/PD-L1 interaction. In addition, the preliminary structure-activity relationships of these new indoline compounds were investigated in this study, providing valuable information for future drug development.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Descubrimiento de Drogas , Indoles/farmacología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Células Jurkat , Simulación del Acoplamiento Molecular , Estructura Molecular , Receptor de Muerte Celular Programada 1/metabolismo , Relación Estructura-ActividadRESUMEN
We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125-0.25⯵g/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.