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1.
Cancer Sci ; 109(11): 3591-3601, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30142229

RESUMEN

Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.


Asunto(s)
Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/administración & dosificación , Animales , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Tumores del Estroma Gastrointestinal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Antimicrob Agents Chemother ; 58(1): 110-9, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24145533

RESUMEN

Dengue virus (DENV) causes disease globally, resulting in an estimated 25 to 100 million new infections per year. No effective DENV vaccine is available, and the current treatment is only supportive. Thus, there is an urgent need to develop therapeutic agents to cure this epidemic disease. In the present study, we identified a potential small-molecule inhibitor, BP13944, via high-throughput screening (HTS) of 60,000 compounds using a stable cell line harboring an efficient luciferase replicon of DENV serotype 2 (DENV-2). BP13944 reduced the expression of the DENV replicon reporter in cells, showing a 50% effective concentration (EC50) of 1.03 ± 0.09 µM. Without detectable cytotoxicity, the compound inhibited replication or viral RNA synthesis in all four serotypes of DENV but not in Japanese encephalitis virus (JEV). Sequencing analyses of several individual clones derived from BP13944-resistant RNAs purified from cells harboring the DENV-2 replicon revealed a consensus amino acid substitution (E66G) in the region of the NS3 protease domain. Introduction of E66G into the DENV replicon, an infectious DENV cDNA clone, and recombinant NS2B/NS3 protease constructs conferred 15.2-, 17.2-, and 3.1-fold resistance to BP13944, respectively. Our results identify an effective small-molecule inhibitor, BP13944, which likely targets the DENV NS3 protease. BP13944 could be considered part of a more effective treatment regime for inhibiting DENV in the future.


Asunto(s)
Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Replicón/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Animales , Cricetinae , Virus del Dengue/enzimología , Farmacorresistencia Viral , Serina Endopeptidasas/metabolismo , Bibliotecas de Moléculas Pequeñas
3.
Antimicrob Agents Chemother ; 57(2): 723-33, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23165461

RESUMEN

Hepatitis C virus (HCV), a member of the Flaviviridae family, affects approximately 3% of the world's population and is becoming the leading cause of liver disease in the world. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In our previous study, we identified a potential HCV NS5A inhibitor, BP008. After further systemic optimization, we discovered a more potent HCV inhibitor, DBPR110. DBPR110 reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and a selective index value of 3.9 ± 0.9 pM and >12,800,000, respectively. DBPR110 reduced HCV2a replicon activity with an EC(50) and a selective index value of 228.8 ± 98.4 pM and >173,130, respectively. Sequencing analyses of several individual clones derived from the DBPR110-resistant RNAs purified from cells harboring genotype 1b and 2a HCV replicons revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. P58L/T and Y93H/N in genotype 1b and T24A, P58L, and Y93H in the genotype 2a replicon were the key substitutions for resistance selection. In the 1b replicon, V153M, M202L, and M265V play a compensatory role in replication and drug resistance. Moreover, DBPR110 displayed synergistic effects with alpha interferon (IFN-α), an NS3 protease inhibitor, and an NS5B polymerase inhibitor. In summary, our results present an effective small-molecule inhibitor, DBPR110, that potentially targets HCV NS5A. DBPR110 could be part of a more effective therapeutic strategy for HCV in the future.


Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/genética , Hepatitis C Crónica/tratamiento farmacológico , Pirrolidinas/farmacología , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Antivirales/química , Línea Celular Tumoral , Genotipo , Hepacivirus/efectos de los fármacos , Hepacivirus/genética , Hepatitis C Crónica/virología , Humanos , Interferón-alfa/farmacología , Mutación , Unión Proteica , ARN Viral/análisis , Replicón , Análisis de Secuencia de ARN , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/genética
4.
Bioorg Med Chem ; 21(11): 2856-67, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23618709

RESUMEN

Preclinical investigations and early clinical trials suggest that FLT3 inhibitors are a viable therapy for acute myeloid leukemia. However, early clinical data have been underwhelming due to incomplete inhibition of FLT3. We have developed 3-phenyl-1H-5-pyrazolylamine as an efficient template for kinase inhibitors. Structure-activity relationships led to the discovery of sulfonamide, carbamate and urea series of FLT3 inhibitors. Previous studies showed that the sulfonamide 4 and carbamate 5 series were potent and selective FLT3 inhibitors with good in vivo efficacy. Herein, we describe the urea series, which we found to be potent inhibitors of FLT3 and VEGFR2. Some inhibited growth of FLT3-mutated MOLM-13 cells more strongly than the FLT3 inhibitors sorafenib (2) and ABT-869 (3). In preliminary in vivo toxicity studies of the four most active compounds, 10f was found to be the least toxic. A further in vivo efficacy study demonstrated that 10f achieved complete tumor regression in a higher proportion of MOLM-13 xenograft mice than 4 and 5 (70% vs 10% and 40%). These results show that compound 10f possesses improved pharmacologic and selectivity profiles and could be more effective than previously disclosed FLT3 inhibitors in the treatment of acute myeloid leukemia.


Asunto(s)
Antineoplásicos/síntesis química , Benzamidas/síntesis química , Benzamidas/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/síntesis química , Urea/análogos & derivados , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Benzamidas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Concentración 50 Inhibidora , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/patología , Ratones , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sensibilidad y Especificidad , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/química
5.
Antimicrob Agents Chemother ; 56(1): 44-53, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22006008

RESUMEN

Hepatitis C virus (HCV) is a global health problem, affecting approximately 3% of the world's population. The standard treatment for HCV infection is often poorly tolerated and ineffective. Therefore, the development of novel or more effective treatment strategies to treat chronic HCV infection is urgently needed. In this report, BP008, a potent small-molecule inhibitor of HCV replication, was developed from a class of compounds with thiazol core structures by means of utilizing a cell-based HCV replicon system. The compound reduced the reporter expression of the HCV1b replicon with a 50% effective concentration (EC(50)) and selective index value of 4.1 ± 0.7 nM and >12,195, respectively. Sequencing analyses of several individual clones derived from BP008-resistant RNAs purified from cells harboring HCV1b replicon revealed that amino acid substitutions mainly within the N-terminal region (domain I) of NS5A were associated with decreased inhibitor susceptibility. Q24L, P58S, and Y93H are the key substitutions for resistance selection; F149L and V153M play the compensatory role in the replication and drug resistance processes. Moreover, BP008 displayed synergistic effects with alpha interferon (IFN-α), NS3 protease inhibitor, and NS5B polymerase inhibitor, as well as good oral bioavailability in SD rats and favorable exposure in rat liver. In summary, our results pointed to an effective small-molecule inhibitor, BP008, that potentially targets HCV NS5A. BP008 can be considered a part of a more effective therapeutic strategy for HCV in the future.


Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Tiazoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sustitución de Aminoácidos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sinergismo Farmacológico , Quimioterapia Combinada , Genes Reporteros , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatitis C Crónica/virología , Hepatocitos/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Interferón-alfa/farmacología , Masculino , Ratas , Replicón , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/metabolismo
6.
Bioorg Med Chem Lett ; 22(14): 4654-9, 2012 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-22726931

RESUMEN

A new class of FLT3 inhibitors has been identified based on the 3-phenyl-1H-5-pyrazolylamine scaffold. The structure-activity relationships led to the discovery of two carbamate series, and some potent compounds within these two series exhibited better growth inhibition of FLT3-mutated MOLM-13 cells than FLT3 inhibitors sorafenib (2) and ABT-869 (3). In particular, compound 8d exhibited the ability to regress tumors in mouse xenograft model using MOLM-13 cells.


Asunto(s)
Aminas/química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Aminas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Humanos , Ratones , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Bioorg Med Chem ; 19(14): 4173-82, 2011 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21708468

RESUMEN

Preclinical investigations and early clinical trial studies suggest that FLT3 inhibitors offer a viable therapy for acute myeloid leukemia. However, early clinical data for direct FLT3 inhibitors provided only modest results because of the failure to fully inhibit FLT3. We have designed and synthesized a novel class of 3-phenyl-1H-5-pyrazolylamine-derived compounds as FLT3 inhibitors which exhibit potent FLT3 inhibition and high selectivity toward different receptor tyrosine kinases. The structure-activity relationships led to the discovery of two series of FLT3 inhibitors, and some potent compounds within these two series exhibited comparable potency to FLT3 inhibitors sorafenib (3) and ABT-869 (4) in both wt-FLT3 enzyme inhibition and FLT3-ITD inhibition on cell growth (MOLM-13 and MV4;11 cells). In particular, the selected compound 12a exhibited the ability to regress tumors in mouse xenograft models using MOLM-13 and MV4;11 cells.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Sulfonamidas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencenosulfonatos/química , Bencenosulfonatos/farmacología , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indazoles/química , Indazoles/farmacología , Ratones , Estructura Molecular , Niacinamida/análogos & derivados , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/química , Piridinas/farmacología , Sorafenib , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Tirosina Quinasa 3 Similar a fms/metabolismo
8.
J Med Chem ; 64(15): 11288-11301, 2021 08 12.
Artículo en Inglés | MEDLINE | ID: mdl-34337952

RESUMEN

Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in one-carbon metabolism. The MTHFD2 gene is upregulated in various cancers but very low or undetectable in normal proliferating cells, and therefore a potential target for cancer treatment. In this study, we present the structure of MTHFD2 in complex with xanthine derivative 15, which allosterically binds to MTHFD2 and coexists with the substrate analogue. A kinetic study demonstrated the uncompetitive inhibition of MTHFD2 by 15. Allosteric inhibitors often provide good selectivity and, indeed, xanthine derivatives are highly selective for MTHFD2. Moreover, several conformational changes were observed upon the binding of 15, which impeded the binding of the cofactor and phosphate to MTHFD2. To the best of our knowledge, this is the first study to identify allosteric inhibitors targeting the MTHFD family and our results would provide insights on the inhibition mechanism of MTHFD proteins and the development of novel inhibitors.


Asunto(s)
Aminohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Metilenotetrahidrofolato Deshidrogenasa (NADP)/antagonistas & inhibidores , Enzimas Multifuncionales/antagonistas & inhibidores , Xantina/farmacología , Sitio Alostérico/efectos de los fármacos , Aminohidrolasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Modelos Moleculares , Estructura Molecular , Enzimas Multifuncionales/metabolismo , Relación Estructura-Actividad , Xantina/síntesis química , Xantina/química
9.
Eur J Med Chem ; 209: 112938, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-33109398

RESUMEN

Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe ß-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as ß-thalassemia and SCD.


Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/síntesis química , Hemoglobina Fetal/metabolismo , Purinas/síntesis química , Talasemia beta/tratamiento farmacológico , Administración Oral , Animales , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/farmacocinética , Permeabilidad de la Membrana Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos , Células Eritroides , Hemoglobina Fetal/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Purinas/administración & dosificación , Purinas/farmacocinética , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad
10.
Life Sci ; 278: 119574, 2021 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-33961850

RESUMEN

AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.


Asunto(s)
Butanos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Nitrilos/farmacología , Pirrolidinas/farmacología , Administración Oral , Animales , Área Bajo la Curva , Peso Corporal , Butanos/farmacocinética , Diabetes Mellitus Experimental/tratamiento farmacológico , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Perros , Prueba de Tolerancia a la Glucosa , Hipoglucemiantes/farmacocinética , Insulina/metabolismo , Venas Yugulares/patología , Masculino , Metformina , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Nitrilos/farmacocinética , Pirrolidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie
11.
Bioorg Med Chem Lett ; 20(12): 3596-600, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20483603

RESUMEN

A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Nitrilos/síntesis química , Pirrolidinas/síntesis química , Administración Oral , Aminas , Animales , Disponibilidad Biológica , Inhibidores de la Dipeptidil-Peptidasa IV/administración & dosificación , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Concentración 50 Inhibidora , Nitrilos/farmacología , Pirrolidinas/farmacología , Ratas , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 19(7): 1908-12, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19269819

RESUMEN

A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Ácido Glutámico/química , Pirrolidinas/síntesis química , Administración Oral , Animales , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Diseño de Fármacos , Glucosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Pirrolidinas/química , Pirrolidinas/farmacología , Relación Estructura-Actividad
13.
Bioorg Med Chem ; 17(6): 2388-99, 2009 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-19261480

RESUMEN

A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.


Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Animales , Dipeptidil Peptidasa 4/sangre , Prueba de Tolerancia a la Glucosa , Espectroscopía de Resonancia Magnética , Ratones , Ratas , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad
14.
Cancers (Basel) ; 11(6)2019 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-31141996

RESUMEN

Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths worldwide. Sorafenib was the only U.S. Food and Drug Administration (FDA) approved drug for treating advanced HCC until recently, so development of new target therapy is urgently needed. In this study, we established a zebrafish drug screening platform and compared the therapeutic effects of two multiple tyrosine kinase inhibitors, 419S1 and 420S1, with Sorafenib. All three compounds exhibited anti-angiogenesis abilities in immersed fli1:EGFP transgenic embryos and the half inhibition concentration (IC50) was determined. 419S1 exhibited lower hepatoxicity and embryonic toxicity than 420S1 and Sorafenib, and the half lethal concentration (LC50) was determined. The therapeutic index (LC50/IC50) for 419S1 was much higher than for Sorafenib and 420S1. The compounds were either injected retro-orbitally or by oral gavage to adult transgenic zebrafish with HCC. The compounds not only rescued the pathological feature, but also reversed the expression levels of cell-cycle-related genes and protein levels of a proliferation marker. Using a patient-derived-xenograft assay, we found that the effectiveness of 419S1 and 420S1 in preventing liver cancer proliferation is better than that of Sorafenib. With integrated efforts and the advantage of the zebrafish platform, we can find more effective and safe drugs for HCC treatment and screen for personalized medicine.

15.
J Med Chem ; 62(8): 3940-3957, 2019 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-30968693

RESUMEN

Drug resistance due to acquired mutations that constitutively activate c-KIT is a significant challenge in the treatment of patients with gastrointestinal stromal tumors (GISTs). Herein, we identified 1-(5-ethyl-isoxazol-3-yl)-3-(4-{2-[6-(4-ethylpiperazin-1-yl)pyrimidin-4-ylamino]-thiazol-5-yl}phenyl)urea (10a) as a potent inhibitor against unactivated and activated c-KIT. The binding of 10a induced rearrangements of the DFG motif, αC-helix, juxtamembrane domain, and the activation loop to switch the activated c-KIT back to its structurally inactive state. To the best of our knowledge, it is the first structural evidence demonstrating how a compound can inhibit the activated c-KIT by switching back to its inactive state through a sequence of conformational changes. Moreover, 10a can effectively inhibit various c-KIT mutants and the proliferation of several GIST cell lines. The distinct binding features and superior inhibitory potency of 10a, together with its excellent efficacy in the xenograft model, establish 10a as worthy of further clinical evaluation in the advanced GISTs.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib/química , Mesilato de Imatinib/metabolismo , Ratones , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/química , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/metabolismo , Urea/farmacología , Urea/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
16.
J Med Chem ; 62(24): 11135-11150, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31721578

RESUMEN

Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a, with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.


Asunto(s)
Antineoplásicos/farmacología , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Pirimidinas/farmacología , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Animales , Antineoplásicos/química , Apoptosis , Proliferación Celular , Femenino , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/enzimología , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/enzimología , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Fosforilación , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/química , Ratas Sprague-Dawley , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/genética
17.
Eur J Med Chem ; 43(8): 1603-11, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18207285

RESUMEN

Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. In our study, 3D pharmacophore models were generated using a training set of 22 DPP-IV inhibitors. The best model consisted of important chemical features and mapped well into the active site of DPP-IV. The model gave high correlation coefficients of 0.97 and 0.84 for the training set and the test set, respectively, showing its good predictive ability for biological activity. Furthermore, the pharmacophore model demonstrated the capability to retrieve inhibitors from database with a high enrichment factor of 42.58. All results suggest that the model provides a useful tool for designing novel DPP-IV inhibitors.


Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Modelos Moleculares , Sitios de Unión , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Humanos , Concentración 50 Inhibidora , Estructura Molecular
18.
J Med Chem ; 49(1): 373-80, 2006 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-16392822

RESUMEN

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.


Asunto(s)
Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Isoquinolinas/farmacología , Pirrolidinonas/farmacología , Administración Oral , Animales , Glucemia/efectos de los fármacos , Dipeptidasas/antagonistas & inhibidores , Dipeptidil Peptidasa 4/sangre , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos , Tolerancia a Medicamentos , Inhibidores Enzimáticos/síntesis química , Glucosa/administración & dosificación , Glucosa/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Isoquinolinas/síntesis química , Masculino , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Pirrolidinonas/síntesis química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Factores de Tiempo
19.
J Med Chem ; 59(8): 3906-19, 2016 04 28.
Artículo en Inglés | MEDLINE | ID: mdl-27031565

RESUMEN

Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Quinasa de Linfoma Anaplásico , Cristalografía por Rayos X , Conformación Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/química , Relación Estructura-Actividad
20.
Mol Cancer Ther ; 15(10): 2323-2333, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27512117

RESUMEN

Acute myelogenous leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. c-KIT mutation can be detected in 17%∼46% of CBF-AML and is associated with poor prognosis. c-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastrointestinal stromal tumors. However, the effect of TKI on c-KIT-driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by the mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell-cycle arrest via targeting aurora kinase B in c-KIT wild-type KG-1 cells. The antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT-driven AML cells via induction of apoptosis and cell-cycle arrest. It is also effective for multiple drug-resistant c-KIT D816V mutation. BPR1J373 deserves further development for clinical use in c-KIT-driven myeloid leukemia. Mol Cancer Ther; 15(10); 2323-33. ©2016 AACR.


Asunto(s)
Leucemia Mieloide Aguda/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mutación , Fosforilación , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-kit/metabolismo , Transducción de Señal/efectos de los fármacos , Activación Transcripcional , Translocación Genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
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