RESUMEN
Inhibitors of apoptosis proteins (IAPs), defined by the presence of baculovirus IAP repeat (BIR) protein domain, are critical regulators of cell survival and cell death processes. Cellular IAP 1/2 (cIAP1/2) and X-linked IAPs (XIAPs) regulate the innate immune signaling pathway through their E3 ubiquitin ligase activity. Peptidomimetics or small-molecule IAP antagonists have been developed to treat various diseases, such as cancer, infection, and inflammation. In this study, we synthesized and characterized IAP-cereblon (CRBN) heterodimerizing proteolysis-targeting chimera (PROTAC), which induces the degradation of cIAP1/2 and XIAP but not CRBN. We demonstrated that this PROTAC inhibits tumor necrosis factor alpha (TNFα)-induced innate immune response and cancer cell migration and invasion, leading to apoptotic cell death. Our study is the first to demonstrate that both cIAPs and XIAP are degradable when applied to the PROTAC strategy.
Asunto(s)
Apoptosis , Transducción de Señal , Muerte Celular , Supervivencia Celular , ProteolisisRESUMEN
AIMS: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS: Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION: Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.
Asunto(s)
Insuficiencia Cardíaca , Ubiquitina-Proteína Ligasas , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Humanos , Ratones , Volumen Sistólico , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , UbiquitinaciónRESUMEN
Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates genes involved in cell lineage and differentiation through methylating lysine 27 on histone H3 (H3K27me3). Recurrent gain-of-function mutations of EZH2 have been identified in various cancer types, in particular, diffuse large B-cell lymphoma (DLBCL), through large-scale genome-wide association studies and EZH2 depletion or pharmacological inhibition has been shown to exert an antiproliferative effect on cancer cells, both in vitro and in vivo. In the current study, a combination of pomalidomide and GSK126 synergistically inhibited the growth of EZH2 gain-of-function mutant Diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, this synergistic effect appeared to be dependent on cereblon (CRBN), a cellular receptor of pomalidomide, but not degradation of IKAROS family zinc finger 1 (IKZF1) or IKAROS family zinc finger 3 (IKZF3). RNA sequencing analyses revealed that co-treatment with GSK126 and pomalidomide induced specific gene sets involved in B-cell differentiation and apoptosis. Synergistic growth inhibition and B-cell differentiation were further validated in xenograft mouse models. Our collective results provide a molecular basis for the mechanisms underlying the combined therapeutic effects of PRC2 inhibitors and pomalidomide on EZH2-mutated DLBCL.
RESUMEN
Triple-negative breast cancer (TNBC) has an aggressive phenotype and poor prognosis due to the lack of specific targeted treatments. The development of an effective therapeutic strategy with a novel mechanism is essential for TNBC management. Olaparib, a PARP inhibitor, has been approved for the treatment of breast or ovarian cancer patients with breast cancer gene 1/2 (BRCA1/2) mutations. Here, we report the development of a small molecule targeting PARP1 based on the hydrophobic tagging (HyT) method. Targeted protein misfolding and consequent degradation are caused by HyT. Hydrophobic-tagged olaparib induces the proteasome-dependent degradation of PARP1 and shows enhanced antitumor effects compared to olaparib in TNBC cells. In addition, hydrophobic-tagged olaparib causes ER stress-related unfolded protein response (UPR), autophagy, and apoptosis. These results point towards encouraging prospects for chemically modifying approved drugs that not only exhibit superior effects compared to those of the original drugs by triggering novel mechanisms but also provide great feasibility in the translational scenario.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/farmacología , Piperazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Respuesta de Proteína Desplegada/efectos de los fármacosRESUMEN
The receptor tyrosine kinase c-MET regulates processes essential for tissue remodeling and mammalian development. The dysregulation of c-MET signaling plays a role in tumorigenesis. The aberrant activation of c-MET, such as that caused by gene amplification or mutations, is associated with many cancers. c-MET is therefore an attractive therapeutic target, and inhibitors are being tested in clinical trials. However, inappropriate patient selection criteria, such as low amplification or expression level cut-off values, have led to the failure of clinical trials. To include patients who respond to MET inhibitors, the selection criteria must include MET oncogenic addiction. Here, the efficacy of ABN401, a MET inhibitor, was investigated using histopathologic and genetic analyses in MET-addicted cancer cell lines and xenograft models. ABN401 was highly selective for 571 kinases, and it inhibited c-MET activity and its downstream signaling pathway. We performed pharmacokinetic profiling of ABN401 and defined the dose and treatment duration of ABN401 required to inhibit c-MET phosphorylation in xenograft models. The results show that the efficacy of ABN401 is associated with MET status and they highlight the importance of determining the cut-off values. The results suggest that clinical trials need to establish the characteristics of each sample and their correlations with the efficacy of MET inhibitors.
RESUMEN
Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and -3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteolisis , Proteínas Recombinantes de Fusión/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Células HEK293 , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Células Jurkat , Dominios Proteicos , Proteínas Recombinantes de Fusión/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.
Asunto(s)
Factores Inmunológicos/farmacología , Péptido Hidrolasas/metabolismo , Proteolisis/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Animales , Línea Celular Tumoral , Femenino , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/química , Ratones , Piperidonas/síntesis química , Piperidonas/química , Piperidonas/farmacología , Ubiquitina-Proteína Ligasas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A novel 6-aminopurine scaffold bearing an N9-cis-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure-activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound 8l displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC50=2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound 81 with CDK2 and CDK5.
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células MCF-7 , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Purinas/síntesis química , Purinas/química , Relación Estructura-ActividadRESUMEN
Human rhinoviruses (hRVs) are the main causative pathogen for common colds and are associated with the exacerbation of asthma. The wide variety in hRV serotypes has complicated the development of rhinovirus replication inhibitors. In the current investigation, we developed a novel series of benzothiophene derivatives and their analogues (6-8) that potently inhibit the replication of both hRV-A and hRV-B strains. Compound 6g inhibited the replication of hRV-B14, A21, and A71, with respective EC50 values of 0.083, 0.078, and 0.015 µM. The results of a time-of-addition study against hRV-B14 and hRV-A16 and resistant mutation analysis on hRV-B14 implied that 6g acts at the early stage of the viral replication process, interacting with viral capsid protein. A molecular docking study suggested that 6g has a capsid-binding mode similar to that of pleconaril. Finally, derivatives of 6 also displayed significant inhibition against poliovirus 3 (PV3) replication, implying their potential inhibitory activities against other enterovirus species.
Asunto(s)
Antivirales/farmacología , Rhinovirus/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Tiofenos/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/química , Replicación Viral/efectos de los fármacosRESUMEN
The piperidine fragment in ceritinib was replaced with diverse aliphatic amines to improve inherent resistance issues of ceritinib. While most of the prepared compounds exhibit as similar in vitro activities as ceritinib, compound 10 shows encouraging activities against wild-type ALK as well as crizotinib-resistant mutants including extremely resistant G1202R mutant with an IC50 of 1.8 nM. Furthermore, pharmacokinetic profiles of 10 is apparently better than that of ceritinib. In murine xenograft studies, compound 10 turns out to be as active as ceritinib, suggesting that further optimization of 10 may lead to clinical candidates overcoming ALK mutant issues.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/química , Pirazoles , Piridinas , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/efectos de los fármacos , Sulfonas/farmacología , Aminas/química , Quinasa de Linfoma Anaplásico , Animales , Crizotinib , Resistencia a Antineoplásicos/genética , Xenoinjertos/efectos de los fármacos , Humanos , Ratones , Mutación , Piperidinas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Pirimidinas/química , Pirimidinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/genética , Sulfonas/química , Sulfonas/farmacocinéticaRESUMEN
Although the ubiquitin-proteasome system is believed to play an important role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS), caused by mutations in Cu/Zn-superoxide dismutase 1 (SOD1), the mechanism of how mutant SOD1 protein is regulated in cells is still poorly understood. Here we have demonstrated that cellular inhibitor of apoptosis proteins (cIAPs) are specifically associated with FALS-linked mutant SOD1 (mSOD1) and that this interaction promotes the ubiquitin-dependent proteasomal degradation of mutant SOD1. By utilizing cumate inducible SOD1 cells, we also showed that knock-down or pharmacologic depletion of cIAPs leads to H2O2 induced cytotoxicity in mSOD1 expressing cells. Altogether, our results reveal a novel role of cIAPs in FALS-associated mutant SOD1 regulation.
Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Esclerosis Amiotrófica Lateral/genética , Células HEK293 , Humanos , Mutación/genética , UbiquitinaciónRESUMEN
A series of pyridazin-3-one substituted with morpholino-pyrimidine derivatives was synthesized and evaluated as tyrosine kinase inhibitors against c-Met enzyme, and anti-proliferative activities of Hs746T human gastric cancer cell line. Most of compounds exhibited good biological activity, while compound 10, 12a, 14a displayed excellent c-Met enzyme inhibitory activities and Hs746T cell-based activities.
Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridazinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Piridazinas/síntesis química , Piridazinas/químicaRESUMEN
BACKGROUND: c-Met signaling has been implicated in oncogenesis especially in cells with c-met gene amplification. Since 20 % of gastric cancer patients show high level of c-Met expression, c-Met has been identified as a good candidate for targeted therapy in gastric cancer. Herein, we report our newly synthesized c-Met inhibitor by showing its efficacy both in vitro and in vivo. METHODS: Compounds with both triazolopyrazine and pyridoxazine scaffolds were synthesized and tested using HTRF c-Met kinase assay. We performed cytotoxic assay, cellular phosphorylation assay, and cell cycle assay to investigate the cellular inhibitory mechanism of our compounds. We also conducted mouse xenograft assay to see efficacy in vivo. RESULTS: KRC-00509 and KRC-00715 were selected as excellent c-Met inhibitors through biochemical assay, and exhibited to be exclusively selective to c-Met by kinase panel assay. Cytotoxic assays using 18 gastric cancer cell lines showed our c-Met inhibitors suppressed specifically the growth of c-Met overexpressed cell lines, not that of c-Met low expressed cell lines, by inducing G1/S arrest. In c-met amplified cell lines, c-Met inhibitors reduced the downstream signals including Akt and Erk as well as c-Met activity. In vivo Hs746T xenograft assay showed KRC-00715 reduced the tumor size significantly. CONCLUSIONS: Our in vitro and in vivo data suggest KRC-00715 is a potent and highly selective c-Met inhibitor which may have therapeutic potential in gastric tumor with c-Met overexpression.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-met/biosíntesis , Pirazinas/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Triazoles/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-met/genética , Pirazinas/síntesis química , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Triazoles/síntesis química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacología , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones Desnudos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.
Asunto(s)
Antineoplásicos/farmacología , Benzazepinas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Neoplasias Experimentales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzazepinas/química , Benzazepinas/farmacocinética , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-ActividadRESUMEN
Here, we show the newly synthesized and potent ALK inhibitor having similar scaffold to KRCA-0008, which was reported previously, and its molecular mechanism against cancer cells harboring EML4-ALK fusion protein. Through ALK wild type enzyme assay, we selected two compounds, KRCA-0080 and KRCA-0087, which have trifluoromethyl instead of chloride in R2 position. We characterized these newly synthesized compounds by in vitro and in vivo assays. Enzyme assay shows that KRCA-0080 is more potent against various ALK mutants, including L1196M, G1202R, T1151_L1152insT, and C1156Y, which are seen in crizotinib-resistant patients, than KRCA-0008 is. Cell based assays demonstrate our compounds downregulate the cellular signaling, such as Akt and Erk, by suppressing ALK activity to inhibit the proliferation of the cells harboring EML4-ALK. Interestingly, our compounds induced strong G1/S arrest in H3122 cells leading to the apoptosis, which is proved by PARP-1 cleavage. In vivo H3122 xenograft assay, we found that KRCA-0080 shows significant reduction in tumor size compared to crizotinib and KRCA-0008 by 15-20%. Conclusively, we report a potent ALK inhibitor which shows significant in vivo efficacy as well as excellent inhibitory activity against various ALK mutants.
Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Crizotinib , Femenino , Humanos , Neoplasias Pulmonares/genética , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/genética , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazoles/farmacología , Piridinas/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report a series of phenyl substituted pyridazin-3-ones substituted with morpholino-pyrimidines. The SAR of the phenyl was explored and their c-Met kinase and cell-based inhibitory activity toward c-Met driven cell lines were evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent morpholino-pyridazinone scaffold, with particular focus on the phenyl and pyrimidine substituents.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridazinas/química , Sitios de Unión , Línea Celular , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-met/metabolismo , Piridazinas/síntesis química , Piridazinas/farmacología , Relación Estructura-ActividadRESUMEN
Erythropoietin-producing hepatocellular receptor tyrosine kinase subtype A2 (EphA2) is an attractive therapeutic target for suppressing tumor progression. In our efforts to discover novel small molecules to inhibit EphA2, a class of compound based on 4-substituted quinazoline containing 7-(morpholin-2-ylmethoxy) group was identified as a novel hit by high throughput screening campaign. Structural modification of parent quinazoline scaffolds by introducing substituents on aniline displayed potent inhibitory activities toward EphA2.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Receptor EphA2/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Quinazolinas/síntesis química , Quinazolinas/química , Receptor EphA2/metabolismo , Relación Estructura-ActividadRESUMEN
Recently some fms-like tyrosine kinase 3 (FLT3) inhibitors have shown good efficacy in acute myeloid leukemia (AML) patients. In an effort to develop anti-leukemic drugs, we investigated quinolinone derivatives as novel FLT3 inhibitors. Two substituted quinolinones, KR65367 and KR65370 were subjected to FLT3 kinase activity assay and showed potent inhibition against FLT3 kinase activity in vitro, with IC50 of 2.7 and 0.57 nM, respectively. As a measure of selectivity, effects on the activity of other kinases were also tested. Both compounds have negligible activity against Met, Ron, epidermal growth factor receptor, Aurora A, Janus kinase 2, and insulin receptor; with IC50 greater than 10 µM. KR compounds showed strong growth inhibition in MV4;11 AML cells and increased the apoptotic cell death in flow cytometric analyses. A decrease in STAT5 phosphorylation by KR compounds was observed in MV4;11 cells. Furthermore, in vitro evaluation of compounds structurally related to KR65367 and KR65370 showed a good structure-activity relationship.