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1.
Bioorg Med Chem Lett ; 80: 129084, 2023 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-36423823

RESUMEN

In the treatment of non-small cell lung cancer (NSCLC), patients harboring exon 20 insertion mutations in the epidermal growth factor receptor (EGFR) gene (EGFR) have few effective therapies because this subset of mutants is generally resistant to most currently approved EGFR inhibitors. This report describes the structure-guided design of a novel series of potent, irreversible inhibitors of EGFR exon 20 insertion mutations, including the V769_D770insASV and D770_N771insSVD mutants. Extensive structure-activity relationship (SAR) studies led to the discovery of mobocertinib (compound 21c), which inhibited growth of Ba/F3 cells expressing the ASV insertion with a half-maximal inhibitory concentration of 11 nM and with selectivity over wild-type EGFR. Daily oral administration of mobocertinib induced tumor regression in a Ba/F3 ASV xenograft mouse model at well-tolerated doses. Mobocertinib was approved in September 2021 for the treatment of adult patients with advanced NSCLC with EGFR exon 20 insertion mutations with progression on or after platinum-based chemotherapy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Ratones , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutagénesis Insercional , Mutación , Receptores ErbB , Exones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
2.
Cancer Discov ; 11(7): 1672-1687, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33632773

RESUMEN

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.


Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Exones , Indoles/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Pirimidinas/uso terapéutico , Compuestos de Anilina/farmacología , Animales , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral/efectos de los fármacos , Receptores ErbB , Humanos , Indoles/farmacología , Neoplasias Pulmonares/genética , Ratones , Mutagénesis Insercional , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Clin Cancer Res ; 22(22): 5527-5538, 2016 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-27780853

RESUMEN

PURPOSE: Non-small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. EXPERIMENTAL DESIGN: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib-ALK co-structure was determined. RESULTS: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. CONCLUSIONS: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527-38. ©2016 AACR.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Crizotinib , Células Hep G2 , Humanos , Neoplasias Pulmonares/metabolismo , Mutación/efectos de los fármacos , Pirazoles/farmacología , Piridinas/farmacología , Sulfonas/farmacología , Células U937
4.
J Med Chem ; 59(10): 4948-64, 2016 05 26.
Artículo en Inglés | MEDLINE | ID: mdl-27144831

RESUMEN

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.


Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organofosforados/farmacología , Fosfinas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Ratones , Ratones SCID , Conformación Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Fosfinas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad
5.
Clin Cancer Res ; 20(22): 5745-5755, 2014 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-25239608

RESUMEN

PURPOSE: KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST. EXPERIMENTAL DESIGN: The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents. RESULTS: In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST. CONCLUSION: Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/genética , Tumores del Estroma Gastrointestinal/genética , Imidazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-kit/genética , Piridazinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Benzamidas/farmacología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Exones , Femenino , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Imidazoles/química , Imidazoles/uso terapéutico , Indoles/farmacología , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Mutación , Recurrencia Local de Neoplasia , Piperazinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/química , Piridazinas/química , Piridazinas/uso terapéutico , Pirimidinas/farmacología , Pirroles/farmacología , Sunitinib , Tomografía Computarizada por Rayos X , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Chem Biol Drug Des ; 78(6): 999-1005, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22034911

RESUMEN

Activating gene rearrangements of anaplastic lymphoma kinase (ALK) have been identified as driver mutations in non-small-cell lung cancer, inflammatory myofibroblastic tumors, and other cancers. Crizotinib, a dual MET/ALK inhibitor, has demonstrated promising clinical activity in patients with non-small-cell lung cancer and inflammatory myofibroblastic tumors harboring ALK translocations. Inhibitors of driver kinases often elicit kinase domain mutations that confer resistance, and such mutations have been successfully predicted using in vitro mutagenesis screens. Here, this approach was used to discover an extensive set of ALK mutations that can confer resistance to crizotinib. Mutations at 16 residues were identified, structurally clustered into five regions around the kinase active site, which conferred varying degrees of resistance. The screen successfully predicted the L1196M, C1156Y, and F1174L mutations, recently identified in crizotinib-resistant patients. In separate studies, we demonstrated that crizotinib has relatively modest potency in ALK-positive non-small-cell lung cancer cell lines. A more potent ALK inhibitor, TAE684, maintained substantial activity against mutations that conferred resistance to crizotinib. Our study identifies multiple novel mutations in ALK that may confer clinical resistance to crizotinib, suggests that crizotinib's narrow selectivity window may underlie its susceptibility to such resistance and demonstrates that a more potent ALK inhibitor may be effective at overcoming resistance.


Asunto(s)
Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas , Línea Celular Tumoral , Crizotinib , Humanos , Neoplasias Pulmonares , Mutación , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo
7.
Bioorg Med Chem Lett ; 21(12): 3743-8, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21561767

RESUMEN

Ponatinib (AP24534) was previously identified as a pan-BCR-ABL inhibitor that potently inhibits the T315I gatekeeper mutant, and has advanced into clinical development for the treatment of refractory or resistant CML. In this study, we explored a novel series of five and six membered monocycles as alternate hinge-binding templates to replace the 6,5-fused imidazopyridazine core of ponatinib. Like ponatinib, these monocycles are tethered to pendant toluanilides via an ethynyl linker. Several compounds in this series displayed excellent in vitro potency against both native BCR-ABL and the T315I mutant. Notably, a subset of inhibitors exhibited desirable PK and were orally active in a mouse model of T315I-driven CML.


Asunto(s)
Alquinos/síntesis química , Alquinos/farmacología , Compuestos de Anilina/síntesis química , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Tolueno/síntesis química , Administración Oral , Alquinos/química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Ciclización , Modelos Animales de Enfermedad , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Ratones , Modelos Moleculares , Estructura Molecular , Mutación , Ratas , Relación Estructura-Actividad , Tolueno/química , Tolueno/farmacología
8.
Mol Cancer Ther ; 10(6): 1059-71, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21482695

RESUMEN

The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analogue that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a range of human tumor types, exploring potential markers of response, and determining optimal dosing regimens to guide clinical studies. Administration of ridaforolimus to tumor cells in vitro elicited dose-dependent inhibition of mTOR activity with concomitant effects on cell growth and division. We showed that ridaforolimus exhibits a predominantly cytostatic mode of action, consistent with the findings for other mTOR inhibitors. Potent inhibitory effects on vascular endothelial growth factor secretion, endothelial cell growth, and glucose metabolism were also observed. Although PTEN and/or phosphorylated AKT status have been proposed as potential mTOR pathway biomarkers, neither was predictive for ridaforolimus responsiveness in the heterogeneous panel of cancer cell lines examined. In mouse models, robust antitumor activity was observed in human tumor xenografts using a series of intermittent dosing schedules, consistent with pharmacodynamic observations of mTOR pathway inhibition for at least 72 hours following dosing. Parallel skin-graft rejection studies established that intermittent dosing schedules lack the immunosuppressive effects seen with daily dosing. Overall these findings show the broad inhibitory effects of ridaforolimus on cell growth, division, metabolism, and angiogenesis, and support the use of intermittent dosing as a means to optimize antitumor activity while minimizing systemic effects.


Asunto(s)
Antibióticos Antineoplásicos/farmacología , Sirolimus/análogos & derivados , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antibióticos Antineoplásicos/administración & dosificación , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Células Endoteliales/efectos de los fármacos , Femenino , Glucosa/metabolismo , Células HCT116 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Proteína Oncogénica v-akt/metabolismo , Fosfohidrolasa PTEN/metabolismo , Fosforilación/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
9.
J Med Chem ; 53(12): 4701-19, 2010 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-20513156

RESUMEN

In the treatment of chronic myeloid leukemia (CML) with BCR-ABL kinase inhibitors, the T315I gatekeeper mutant has emerged as resistant to all currently approved agents. This report describes the structure-guided design of a novel series of potent pan-inhibitors of BCR-ABL, including the T315I mutation. A key structural feature is the carbon-carbon triple bond linker which skirts the increased bulk of Ile315 side chain. Extensive SAR studies led to the discovery of development candidate 20g (AP24534), which inhibited the kinase activity of both native BCR-ABL and the T315I mutant with low nM IC(50)s, and potently inhibited proliferation of corresponding Ba/F3-derived cell lines. Daily oral administration of 20g significantly prolonged survival of mice injected intravenously with BCR-ABL(T315I) expressing Ba/F3 cells. These data, coupled with a favorable ADME profile, support the potential of 20g to be an effective treatment for CML, including patients refractory to all currently approved therapies.


Asunto(s)
Antineoplásicos/síntesis química , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Imidazoles/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Piridazinas/síntesis química , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Proteínas de Fusión bcr-abl/genética , Imidazoles/farmacocinética , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Ratones , Ratones SCID , Modelos Moleculares , Mutación , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/farmacocinética , Piridazinas/farmacología , Ratas
10.
Cancer Cell ; 16(5): 401-12, 2009 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-19878872

RESUMEN

Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL(T315I) mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL(T315I)-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.


Asunto(s)
Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Imidazoles/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Piridazinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Cristalografía por Rayos X , Proteínas de Fusión bcr-abl/química , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Imidazoles/química , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ratones , Ratones SCID , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-abl/química , Proteínas Proto-Oncogénicas c-abl/genética , Proteínas Proto-Oncogénicas c-abl/metabolismo , Piridazinas/química , Transducción de Señal/efectos de los fármacos
11.
J Med Chem ; 52(15): 4743-56, 2009 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-19572547

RESUMEN

A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia.


Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Purinas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Animales , Femenino , Humanos , Células K562 , Ratones , Células 3T3 NIH , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/química , Purinas/farmacología , Ratas , Relación Estructura-Actividad , Familia-src Quinasas/química
12.
Bioorg Med Chem Lett ; 18(17): 4907-12, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18691885

RESUMEN

Novel N(9)-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N(9) on the purine core which projects hydrophobic substituents into the selectivity pocket at the rear of the ATP site. Their synthesis was achieved through a Horner-Wadsworth-Emmons reaction of N(9)-phosphorylmethylpurines and substituted benzaldehydes or Heck reactions between 9-vinyl purines and aryl halides. Most compounds are potent inhibitors of both Src and Abl kinase, and several possess good oral bioavailability.


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores de Crecimiento/química , Inhibidores de Crecimiento/farmacología , Humanos , Células K562 , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-abl/fisiología , Ratas
13.
Toxicol Appl Pharmacol ; 218(3): 256-64, 2007 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17222881

RESUMEN

Alveolar macrophages (AMs) primed with LPS and treated with concentrated ambient air particles (CAPs) showed enhanced release of tumor necrosis factor (TNF) and provide an in vitro model for the amplified effects of air pollution particles seen in people with preexisting lung disease. To investigate the mechanism(s) by which CAPs mediate TNF release in primed rat AMs, we first tested the effect of a panel of antioxidants. N-Acetyl-l-cysteine (20 mM), dimethyl thiourea (20 mM) and catalase (5 microM) significantly inhibited TNF release by primed AMs incubated with CAPs. Conversely, when LPS-primed AMs were treated with CAPs in the presence of exogenous oxidants (H(2)O(2) generated by glucose oxidase, 10 microM/h), TNF release and cell toxicity was significantly increased. The soluble fraction of CAPs suspensions caused most of the increased bioactivity in the presence of exogenous H(2)O(2). The metal chelator deferoxamine (DFO) strongly inhibited the interaction of the soluble fraction with H(2)O(2) but had no effect on the bioactivity of the insoluble CAPs fraction. We conclude that CAPs can mediate their effects in primed AMs by acting on oxidant-sensitive cytokine release in at least two distinct ways. In the primed cell, insoluble components of PM mediate enhanced TNF production that is H(2)O(2)-dependent (catalase-sensitive) yet independent of iron (DFO-insensitive). In the presence of exogenous H(2)O(2) released by AMs, PMNs, or other lung cells within an inflamed alveolar milieu, soluble iron released from air particles can also mediate cytokine release and cell toxicity.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Macrófagos Alveolares/efectos de los fármacos , Material Particulado/toxicidad , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antioxidantes/farmacología , Catalasa/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Deferoxamina/farmacología , Combinación de Medicamentos , Femenino , Peróxido de Hidrógeno/farmacología , Lipopolisacáridos/farmacología , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patología , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Ratas , Ratas Endogámicas , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores
14.
Am J Respir Cell Mol Biol ; 35(4): 474-8, 2006 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16675784

RESUMEN

The class A macrophage scavenger receptor SR-AI/II is implicated as a pattern recognition receptor for innate immunity, but its functional role in lung defense has not been studied. We used mice genetically deficient in SR-AI/II and their wild-type C57BL/6 counterparts to investigate the contribution of this receptor to defense against pneumococcal infection and inhaled particles. SR-AI/II deficiency caused impaired phagocytosis of fluorescent bacteria in vivo, diminished clearance of live bacteria from the lungs, and substantially increased pneumonic inflammation. Survival studies also showed increased mortality in SR-AI/II-deficient mice with pneumococcal lung infection. Similarly, after challenge of the airways with TiO(2) particles, SR-AI/II-deficient mice showed increased proinflammatory cytokine levels in lung lavage fluid and a more pronounced neutrophilic inflammation. The data indicate that the lung macrophage class A scavenger receptor SR-AI/II contributes to innate defense against bacteria and inhaled particles.


Asunto(s)
Inmunidad Innata , Pulmón/inmunología , Neumonía Neumocócica/inmunología , Receptores Depuradores de Clase A/fisiología , Animales , Susceptibilidad a Enfermedades , Femenino , Pulmón/metabolismo , Pulmón/microbiología , Macrófagos Alveolares/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fagocitosis , Neumonía Neumocócica/mortalidad , Receptores Depuradores de Clase A/genética , Titanio/farmacología
15.
J Exp Med ; 200(2): 267-72, 2004 Jul 19.
Artículo en Inglés | MEDLINE | ID: mdl-15263032

RESUMEN

Alveolar macrophages (AMs) express the class A scavenger receptor macrophage receptor with collagenous structure (MARCO), but its role in vivo in lung defense against bacteria and environmental particles has not been studied. We used MARCO-deficient mice to directly test the in vivo role of AM MARCO in innate defense against pneumococcal infection and environmental particles. In a murine model of pneumococcal pneumonia, MARCO(-/-) mice displayed an impaired ability to clear bacteria from the lungs, increased pulmonary inflammation and cytokine release, and diminished survival. In vitro binding of Streptococcus pneumoniae and in vivo uptake of unopsonized particles by MARCO(-/-) AMs were dramatically impaired. MARCO(-/-) mice treated with the "inert" environmental particle TiO(2) showed enhanced inflammation and chemokine expression, indicating that MARCO-mediated clearance of inert particles by AMs prevents inflammatory responses otherwise initiated by other lung cells. Our findings point to an important role of MARCO in mounting an efficient and appropriately regulated innate immune response against inhaled particles and airborne pathogens.


Asunto(s)
Pulmón/inmunología , Macrófagos Alveolares/inmunología , Neumonía Neumocócica/inmunología , Receptores Inmunológicos/metabolismo , Animales , Lavado Broncoalveolar , Líquido del Lavado Bronquioalveolar , Supervivencia Celular , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunidad Innata , Inflamación , Pulmón/citología , Pulmón/microbiología , Pulmón/patología , Macrófagos/patología , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fagocitosis , Neumonía Neumocócica/microbiología , Unión Proteica , Streptococcus pneumoniae/metabolismo , Factores de Tiempo , Titanio/farmacología
16.
Am J Respir Cell Mol Biol ; 30(5): 744-50, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-14630611

RESUMEN

Exposure to ambient air pollution particles causes greater health effects in individuals with preexisting inflammatory lung diseases. To model inflammatory priming in vitro, HTB54 lung epithelial cells were pretreated with tumor necrosis factor-alpha (TNF-alpha) and then exposed to a panel of environmental particles, including concentrated ambient particles (CAPs). TNF-alpha priming significantly enhanced interleukin (IL)-8 secretion in response to CAPs and other urban air particles in HTB54 cells. Enhancement was seen with whole CAP suspensions as well as with its separate water-soluble and -insoluble components. Treating CAP suspensions with 20 microM deferoxamine or 2 mM dimethylthiourea attenuated the enhancement, indicating that transition metals and oxidative stress participate in the CAPs-dependent IL-8 response of primed cells. Because activated neutrophils are also present in diseased lungs and are sources of additional oxidative stress on epithelial cells, primed HTB54 cells were cocultured with activated neutrophils. Wild-type neutrophils markedly enhanced IL-8 release to CAPs in primed HTB54 cells, an effect substantially diminished when neutrophils from NADPH knockout mice were used. Cytokine priming and interactions with activated neutrophils can amplify lung epithelial inflammatory responses to ambient air particles.


Asunto(s)
Contaminantes Atmosféricos/farmacología , Células Epiteliales/efectos de los fármacos , Interleucina-8/metabolismo , Activación Neutrófila , Neutrófilos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Contaminantes Atmosféricos/metabolismo , Animales , Antioxidantes/farmacología , Línea Celular Tumoral , Células Cultivadas , Técnicas de Cocultivo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Humanos , Exposición por Inhalación , Interleucina-8/inmunología , Macrófagos Alveolares/metabolismo , Metales/farmacología , Ratones , Ratones Noqueados , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Activación Neutrófila/inmunología , Neutrófilos/citología , Neutrófilos/inmunología , Oxidantes/farmacología , Estrés Oxidativo , Tamaño de la Partícula , Ratas , Factor de Necrosis Tumoral alfa/inmunología
17.
Inhal Toxicol ; 14(4): 325-47, 2002 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12028808

RESUMEN

We investigated whether coexposure to inhaled ambient particles and ozone affects airway responsiveness (AR, measured as enhanced pause, Penh) and allergic inflammation (AI) in a murine model of asthma. Ovalbumin-sensitized mice were challenged with either ovalbumin ("asthmatic") or phosphate-buffered saline (PBS) aerosols for 3 successive days. Immediately after daily challenge, mice were exposed for 5 h to concentrated ambient particles (CAPs), or 0.3 ppm ozone, or both, or neither (n > or = 61/group, 12 experiments). Exposure to CAPs alone or coexposure to CAPs + O(3) caused an increase in Penh in both normal and "asthmatic" mice. These responses were transient and small, increasing approximately 0.9% per 100-microg/m(3) increase in CAPs. Analysis of the effects of particle composition on AR revealed an association between the AlSi particle fraction and increased AR in "asthmatic" mice exposed to ozone and particles. No effects of pollutants on AI were noted. We conclude that (1) particle exposure causes an immediate, short-lived (<24 h) increase in AR in mice; (2) these responses are small; and (3) changes in AR may be correlated with specific elements within the particle mixture.


Asunto(s)
Contaminantes Atmosféricos/efectos adversos , Asma/fisiopatología , Exposición a Riesgos Ambientales , Pulmón/patología , Oxidantes Fotoquímicos/efectos adversos , Ozono/efectos adversos , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Inflamación , Tamaño de la Partícula
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