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1.
Chirality ; 34(11): 1437-1452, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35959859

RESUMEN

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.


Asunto(s)
Alcaloides , Antineoplásicos , Alcaloides/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/química , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Estereoisomerismo , Relación Estructura-Actividad
2.
Mol Cancer Ther ; 17(3): 603-613, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29237806

RESUMEN

Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRß, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRß inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC50s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models in vivo In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma. Mol Cancer Ther; 17(3); 603-13. ©2017 AACR.


Asunto(s)
Afatinib/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Cordoma/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Proteínas Fetales/antagonistas & inhibidores , Proteínas de Dominio T Box/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cordoma/genética , Cordoma/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas Fetales/genética , Proteínas Fetales/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones Desnudos , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética
3.
Sci Rep ; 7(1): 9226, 2017 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-28835717

RESUMEN

Chordomas are rare, slowly growing tumors with high medical need, arising in the axial skeleton from notochord remnants. The transcription factor "brachyury" represents a distinctive molecular marker and a key oncogenic driver of chordomas. Tyrosine kinase receptors are also expressed, but so far kinase inhibitors have not shown clear clinical efficacy in chordoma patients. The need for effective therapies is extremely high, but the paucity of established chordoma cell lines has limited preclinical research. Here we describe the isolation of the new Chor-IN-1 cell line from a recurrent sacral chordoma and its characterization as compared to other chordoma cell lines. Chor-IN-1 displays genomic identity to the tumor of origin and has morphological features, growth characteristics and chromosomal abnormalities typical of chordoma, with expression of brachyury and other relevant biomarkers. Chor-IN-1 gene variants, copy number alterations and kinome gene expression were analyzed in comparison to other four chordoma cell lines, generating large scale DNA and mRNA genomic data that can be exploited for the identification of novel pharmacological targets and candidate predictive biomarkers of drug sensitivity in chordoma. The establishment of this new, well characterized chordoma cell line provides a useful tool for the identification of drugs active in chordoma.


Asunto(s)
Cordoma/genética , Genómica , Biopsia , Línea Celular Tumoral , Cordoma/metabolismo , Cordoma/patología , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Humanos , Inmunohistoquímica , Cariotipo , Masculino , Persona de Mediana Edad
4.
J Med Chem ; 57(24): 10443-54, 2014 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-25474526

RESUMEN

Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.


Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Adenosina Trifosfatasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células HCT116 , Humanos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad , Proteína que Contiene Valosina
5.
Bioorg Med Chem ; 21(23): 7364-80, 2013 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-24139169

RESUMEN

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-pim-1/antagonistas & inhibidores , Pirazinas/química , Pirazinas/farmacología , Descubrimiento de Drogas , Humanos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-pim-1/química , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Pirazinas/síntesis química
6.
Mol Divers ; 16(1): 27-51, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22350112

RESUMEN

The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.


Asunto(s)
Adenosina Trifosfato/análogos & derivados , Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/farmacología , Sitios de Unión , Bases de Datos como Asunto , Ensayos Analíticos de Alto Rendimiento , Modelos Moleculares , Inhibidores de Proteínas Quinasas/análisis , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirazoles/química , Estándares de Referencia
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