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1.
AAPS PharmSciTech ; 22(3): 101, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712968

RESUMEN

There is an increasing need to develop improved and non-invasive strategies to treat spinal cord injury (SCI). Nanoparticles (NPs) are an enabling technology to improve drug delivery, modulate inflammatory responses, and restore functional responses following SCI. However, the complex pathophysiology associated with SCI presents several distinct challenges that must be overcome for sufficient NP drug delivery to the spinal cord. The objective of this mini-review is to highlight the physiological challenges and cell types available for modulation and discuss several promising advancements using NPs to improve SCI treatment. We will focus our discussion on recent innovative approaches in NP drug delivery and how the implementation of multifactorial approaches to address the proinflammatory and complex immune dysfunction in SCI offers significant potential to improve outcomes in SCI.


Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Humanos
2.
Biochem Soc Trans ; 48(6): 2691-2701, 2020 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-33242077

RESUMEN

Oncogenic mutation in KRAS is one of the most common alterations in human cancer. After decades of extensive research and unsuccessful drug discovery programs, therapeutic targeting of KRAS mutant tumour is at an exciting juncture. The discovery of mutation-specific inhibitors of KRASG12C and early positive findings from clinical trials has raised the hope of finally having a drug to treat a significant segment of KRAS mutant cancer patients. Crucially, it has also re-energized the RAS field to look beyond G12C mutation and find new innovative targeting opportunities. However, the early clinical trial data also indicates that there is significant variation in response among patients and that monotherapy treatment with KRASG12C inhibitors (G12Ci) alone is unlikely to be sufficient to elicit a sustained response. Understanding the molecular mechanism of variation in patient response and identifying possible combination opportunities, which could be exploited to achieve durable and significant responses and delay emergence of resistance, is central to the success of G12Ci therapy. Given the specificity of G12Ci, toxicity is expected to be minimal. Therefore, it might be possible to combine G12Ci with other targeted agents which have previously been explored to tackle KRAS mutant cancer but deemed too toxic, e.g. MEK inhibitor. Ongoing clinical trials will shed light on clinical resistance to G12C inhibitors, however extensive work is already ongoing to identify the best combination partners. This review provides an update on combination opportunities which could be explored to maximize the benefit of this new exciting drug.


Asunto(s)
Regulación de la Expresión Génica , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Animales , Antineoplásicos/uso terapéutico , Apoptosis , Autofagia , Línea Celular Tumoral , Linaje de la Célula , Proliferación Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Diseño de Fármacos , Epigénesis Genética , Humanos , Sistema Inmunológico , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Proteínas ras/metabolismo
3.
Biochem Soc Trans ; 46(5): 1303-1311, 2018 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-30154091

RESUMEN

Oncogenic mutations in RAS genes underlie the pathogenesis of many human tumours, and there has been intense effort for over 30 years to develop effective and tolerated targeted therapeutics for patients with Ras-driven cancers. This review summarises the progress made in Ras drug discovery, highlighting some of the recent developments in directly targeting Ras through advances in small molecule drug design and novel therapeutic strategies.


Asunto(s)
Terapia Molecular Dirigida/métodos , Neoplasias/genética , Proteínas ras/metabolismo , Animales , Antineoplásicos/uso terapéutico , Diseño de Fármacos , Descubrimiento de Drogas , Genes ras , Humanos , Ratones , Mutación , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Oligonucleótidos Antisentido/genética , Procesamiento Proteico-Postraduccional , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos
4.
Langmuir ; 34(45): 13461-13471, 2018 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-29699394

RESUMEN

Chemically and biochemically functionalized colloidal nanoparticles with appropriate surface chemistry are essential for various biomedical applications. Although a variety of approaches are now available in making such functional nanoparticles and nanobioconjugates, the lack of complementary surface chemistry often leads to poor performance with respect to intended biomedical applications. This feature article will focus on our efforts to make colloidal nanobioconjugates with appropriate/complementary surface chemistry for better performance of a designed nanoprobe with respect to cellular and subcellular targeting applications. In particular, we emphasize polyacrylate-based coating chemistry followed by a conjugation strategy for transforming <10 nm inorganic nanoparticle to colloidal nanoprobe of 20-50 nm hydrodynamic size. We show that a colloidal nanoprobe can be chemically designed to control the cell-nanoparticle interaction, cellular endocytosis, and targeting/labeling of subcellular compartments. Further study should be directed to adapt this surface chemistry to different nanoparticles, fine tune the surface chemistry for targeting/imaging on the subcellular/molecular length scale, and develop a delivery nanocarrier for subcellular compartments.


Asunto(s)
Resinas Acrílicas/química , Coloides/química , Nanoconjugados/química , Nanopartículas/química , Orgánulos/metabolismo , Endocitosis/efectos de los fármacos , Células HeLa , Humanos , Tamaño de la Partícula , Multimerización de Proteína/efectos de los fármacos , Propiedades de Superficie
5.
EMBO J ; 32(11): 1556-67, 2013 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-23624934

RESUMEN

c-Jun, the major component of the AP-1 transcription factor complex, has important functions in cellular proliferation and oncogenic transformation. The RING domain-containing protein RACO-1 functions as a c-Jun coactivator that molecularly links growth factor signalling to AP-1 transactivation. Here we demonstrate that RACO-1 is present as a nuclear dimer and that c-Jun specifically interacts with dimeric RACO-1. Moreover, RACO-1 is identified as a substrate of the arginine methyltransferase PRMT1, which methylates RACO-1 on two arginine residues. Arginine methylation of RACO-1 promotes a conformational change that stabilises RACO-1 by facilitating K63-linked ubiquitin chain formation, and enables RACO-1 dimerisation and c-Jun interaction. Abrogation of PRMT1 function impairs AP-1 activity and results in decreased expression of a large percentage of c-Jun target genes. These results demonstrate that arginine methylation of RACO-1 is required for efficient transcriptional activation by c-Jun/AP-1 and thus identify PRMT1 as an important regulator of c-Jun/AP-1 function.


Asunto(s)
Arginina/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas Represoras/metabolismo , Transactivadores/metabolismo , Factor de Transcripción AP-1/metabolismo , Activación Transcripcional , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Núcleo Celular/metabolismo , Proliferación Celular , Transformación Celular Neoplásica , Dimerización , Células HEK293 , Humanos , Metilación , Regiones Promotoras Genéticas/genética , Unión Proteica , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-jun/genética , Conejos , Transducción de Señal , Transactivadores/genética , Factor de Transcripción AP-1/genética , Ubiquitina-Proteína Ligasas/genética
6.
Nature ; 469(7329): 231-5, 2011 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-21196933

RESUMEN

AP-1 (activator protein 1) activity is strongly induced in response to numerous signals, including growth factors, cytokines and extracellular stresses. The proto-oncoprotein c-Jun belongs to the AP-1 group of transcription factors and it is a crucial regulator of intestinal progenitor proliferation and tumorigenesis. An important mechanism of AP-1 stimulation is phosphorylation of c-Jun by the Jun amino-terminal kinases (JNKs). N-terminal phosphorylation of the c-Jun transactivation domain increases target gene transcription, but a molecular explanation was elusive. Here we show that unphosphorylated, but not N-terminally phosphorylated c-Jun, interacts with Mbd3 and thereby recruits the nucleosome remodelling and histone deacetylation (NuRD) repressor complex. Mbd3 depletion in colon cancer cells increased histone acetylation at AP-1-dependent promoters, which resulted in increased target gene expression. The intestinal stem cell marker lgr5 was identified as a novel target gene controlled by c-Jun/Mbd3. Gut-specific conditional deletion of mbd3 (mbd3(ΔG/ΔG) mice) stimulated c-Jun activity and increased progenitor cell proliferation. In response to inflammation, mdb3 deficiency resulted in colonic hyperproliferation and mbd3(ΔG/ΔG) mice showed markedly increased susceptibility to colitis-induced tumorigenesis. Notably, concomitant inactivation of a single allele of c-jun reverted physiological and pathological hyperproliferation, as well as the increased tumorigenesis in mbd3(ΔG/ΔG) mice. Thus the transactivation domain of c-Jun recruits Mbd3/NuRD to AP-1 target genes to mediate gene repression, and this repression is relieved by JNK-mediated c-Jun N-terminal phosphorylation.


Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/antagonistas & inhibidores , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Proteínas Proto-Oncogénicas c-jun/química , Proteínas Proto-Oncogénicas c-jun/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Acetilación , Animales , Línea Celular Tumoral , Proliferación Celular , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Proteínas de Unión al ADN/deficiencia , Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Intestinos/citología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/química , Ratones , Fosforilación , Regiones Promotoras Genéticas/genética , Unión Proteica , Receptores Acoplados a Proteínas G/genética , Células Madre/citología , Factores de Transcripción/deficiencia
7.
Phys Chem Chem Phys ; 16(24): 12291-8, 2014 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-24818714

RESUMEN

We use a femtosecond pump-probe Z-scan technique to measure the thermal lens (TL) signal in a homologous series of primary alcohols. The trend in these experimentally measured TL signals deviates in a counterintuitive manner from the ones calculated using theoretical models that are only based on the macroscopic parameters. Introspection shows that the present TL theories are based on heat conduction for low absorbing samples without considering any convective mode of heat transfer. Our studies on highly absorbing samples indicate the importance of convective mode of heat transfer in TL studies.

8.
Mol Microbiol ; 80(5): 1169-85, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21435034

RESUMEN

Transcription activator C employs a unique mechanism to activate mom gene of bacteriophage Mu. The activation process involves, facilitating the recruitment of RNA polymerase (RNAP) by altering the topology of the promoter and enhancing the promoter clearance by reducing the abortive transcription. To understand the basis of this multi-step activation mechanism, we investigated the nature of the physical interaction between C and RNAP during the process. A variety of assays revealed that only DNA-bound C contacts the ß' subunit of RNAP. Consistent to these results, we have also isolated RNAP mutants having mutations in the ß' subunit which were compromised in C-mediated activation. Mutant RNAPs show reduced productive transcription and increased abortive initiation specifically at the C-dependent mom promoter. Positive control (pc) mutants of C, defective in interaction with RNAP, retained the property of recruiting RNAP to the promoter but were unable to enhance promoter clearance. These results strongly suggest that the recruitment of RNAP to the mom promoter does not require physical interaction with C, whereas a contact between the ß' subunit and the activator, and the subsequent allosteric changes in the active site of the enzyme are essential for the enhancement of promoter clearance.


Asunto(s)
Bacteriófago mu/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , ARN Polimerasas Dirigidas por ADN/genética , ARN Polimerasas Dirigidas por ADN/metabolismo , Escherichia coli/enzimología , Regiones Promotoras Genéticas , Activación Transcripcional , Proteínas Virales/metabolismo , Secuencias de Aminoácidos , Bacteriófago mu/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Sitios de Unión , ARN Polimerasas Dirigidas por ADN/química , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/virología , Regulación Viral de la Expresión Génica , Mutación , Unión Proteica , Transactivadores/genética , Transactivadores/metabolismo , Transcripción Genética , Proteínas Virales/genética
9.
ACS Appl Mater Interfaces ; 14(51): 56440-56453, 2022 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-36525379

RESUMEN

Extrahepatic nucleic acid delivery using polymers typically requires the synthesis and purification of custom monomers, post-synthetic modifications, and incorporation of additional excipients to augment their stability, endosomal escape, and in vivo effectiveness. Here, we report the development of a single-component and excipient-free, polyester-based nucleic acid delivery nanoparticle platform comprising ionizable N-methyldiethanolamine (MDET) and various hydrophobic alkyl diols (Cp) that achieves lung-selective nucleic acid transfection in vivo. PolyMDET and polyMDET-Cp polyplexes displayed high serum and enzymatic stability, while delivering pDNA or mRNA to "hard-to-transfect" innate immune cells. PolyMDET-C4 and polyMDET-C6 mediated high protein expression in lung alveolar macrophages and dendritic cells without inducing tissue damage or systemic inflammatory responses. Improved strategies using readily available starting materials to produce a simple, excipient-free, non-viral nucleic acid delivery platform with lung-selective and innate immune cell tropism has the potential to expedite clinical deployment of polymer-based genetic medicines.


Asunto(s)
Nanopartículas , Poliésteres , ARN Mensajero/genética , ARN Mensajero/química , Transfección , Plásmidos/genética , ADN/química , Polímeros/química , Pulmón/metabolismo , Nanopartículas/química , Inmunidad Innata
10.
Sci Rep ; 12(1): 2699, 2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-35177674

RESUMEN

The development of covalent inhibitors against KRAS G12C represents a major milestone in treatment of RAS-driven cancers, especially in non-small cell lung cancer (NSCLC), where KRAS G12C is one of the most common oncogenic driver. Here we investigated if additional KRAS mutations co-occur with KRAS G12C (c.34G>T) in NSCLC tumours and if such mutation co-occurrence affects cellular response to G12C-specific inhibitors. Analysis of a large cohort of NSCLC patients whose tumours harboured KRAS mutations revealed co-occurring KRAS mutations in up to 8% of tumours with the KRAS c.34G>T mutation. KRAS c.35G>T was the most frequently co-occurring mutation, and could occur on the same allele (in cis) translating to a single mutant KRAS G12F protein, or on the other allele (in trans), translating to separate G12C and G12V mutant proteins. Introducing KRAS c.35G>T in trans in the KRAS G12C lung cancer model NCI-H358, as well as the co-occurrence in cis in the KRAS G12F lung cancer model NCI-H2291 led to cellular resistance to the G12C-specific inhibitor AZ'8037 due to continuing active MAPK and PI3K cascades in the presence of the inhibitor. Overall, our study provides a comprehensive assessment of co-occurring KRAS mutations in NSCLC and in vitro evidence of the negative impact of co-occurring KRAS mutations on cellular response to G12C inhibitors, highlighting the need for a comprehensive KRAS tumour genotyping for optimal patient selection for treatment with a KRAS G12C inhibitor.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Tasa de Mutación , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Estudios Retrospectivos
11.
Mol Cancer Ther ; 21(10): 1535-1546, 2022 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-35930755

RESUMEN

AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays and in vivo in preclinical cell line-derived and patient-derived xenograft models. In vitro and cellular assays have shown selective binding and inhibition of the KRASG12C mutant isoform, which carries a glycine to cysteine mutation at residue 12, with no binding and inhibition of wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology of AZD4625 shows that it has the potential to provide therapeutic benefit to patients with KRASG12C mutant cancer as either a monotherapy treatment or in combination with other targeted drug agents.


Asunto(s)
Antineoplásicos , Cisteína , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Glicina/farmacología , Humanos , Mutación , Isoformas de Proteínas , Ensayos Antitumor por Modelo de Xenoinjerto
12.
J Med Chem ; 65(9): 6940-6952, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35471939

RESUMEN

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/farmacología , Diseño de Fármacos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinazolinas/farmacología , Relación Estructura-Actividad
13.
JCI Insight ; 6(13)2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34236045

RESUMEN

The AP-1 transcription factor c-Jun is required for Ras-driven tumorigenesis in many tissues and is considered as a classical proto-oncogene. To determine the requirement for c-Jun in a mouse model of K-RasG12D-induced lung adenocarcinoma, we inducibly deleted c-Jun in the adult lung. Surprisingly, we found that inactivation of c-Jun, or mutation of its JNK phosphorylation sites, actually increased lung tumor burden. Mechanistically, we found that protein levels of the Jun family member JunD were increased in the absence of c-Jun. In c-Jun-deficient cells, JunD phosphorylation was increased, and expression of a dominant-active JNKK2-JNK1 transgene further increased lung tumor formation. Strikingly, deletion of JunD completely abolished Ras-driven lung tumorigenesis. This work identifies JunD, not c-Jun, as the crucial substrate of JNK signaling and oncogene required for Ras-induced lung cancer.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinogénesis , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas ras/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Silenciador del Gen , Genes jun/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MAP Quinasa Quinasa 7/genética , MAP Quinasa Quinasa 7/metabolismo , Sistema de Señalización de MAP Quinasas , Ratones , Fosforilación , Proteínas Proto-Oncogénicas c-jun/genética , Factor de Transcripción AP-1/metabolismo
14.
ACS Appl Bio Mater ; 3(9): 6263-6272, 2020 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-34604713

RESUMEN

Genetic engineering of innate and adaptive immune cells represents a potential solution to treat numerous immune-mediated pathologies. Current immune engineering methods to introduce nucleic acids into cells with high efficiency rely on physical mechanisms such as electroporation, viral vectors, or other chemical methods. Gene delivery using non-viral nanoparticles offers significant flexibility in biomaterial design to tune critical parameters such as nano-bio interactions, transfection efficiency, and toxicity profiles. However, their clinical utility has been limited due to complex synthetic procedures, high toxicity at increased polymer (nitrogen, N) to DNA ratios (phosphate, P) (N/P ratios), poor transfection efficiency and nanoparticle stability in the presence of serum, and short-term gene expression. Here, we describe the development of a simple, polymer-based non-viral gene delivery platform based on simple modifications of polyethylenimine (PEI) that displays potent and serum-independent transfection of innate and adaptive immune cells. Cationic acetylated PEI (Ac-PEI) was synthesized and complexed with plasmid DNA (pDNA) followed by enveloping with an anionic polyelectrolyte layer of poly(ethylene-alt-maleic acid) (PEMA) to form immunoplexes (IPs). Cellular interactions and gene expression could be precisely controlled in murine RAW 264.7 macrophages, murine DC2.4 dendritic cells, and human Jurkat T cells by altering the levels of PEMA envelopment, thus providing a strategy to engineer specific cell targeting into the IP platform. Optimally formulated IPs for immune cell transfection in the presence of serum utilized high N/P ratios to enable high stability, displayed reduced toxicity, high gene expression, and a lengthened duration of gene expression (>3 days) compared to non-enveloped controls. These results demonstrate the potential of engineered IPs to serve as simple, modular, targetable, and efficient non-viral gene delivery platform to efficiently alter gene expression within cells of the immune system.

15.
J Tissue Eng ; 11: 2041731419897460, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32180936

RESUMEN

Brain diseases including neurodegenerative disorders and tumours are among the most serious health problems, degrading the quality of life and causing massive economic cost. Nanoparticles that load and deliver drugs and genes have been intensively studied for the treatment of brain diseases, and have demonstrated some biological effects in various animal models. Among other efforts taken in the nanoparticle development, targeting of blood brain barrier, specific cell type or local intra-/extra-cellular space is an important strategy to enhance the therapeutic efficacy of the nanoparticle delivery systems. This review underlies the targeting issue in the nanoparticle development for the treatment of brain diseases, taking key exemplar studies carried out in various in vivo models.

16.
J Med Chem ; 63(9): 4468-4483, 2020 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-32023060

RESUMEN

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Quinolonas/uso terapéutico , Regulación Alostérica , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Células CACO-2 , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Masculino , Ratones Desnudos , Conformación Molecular , Mutación , Piperazinas/síntesis química , Piperazinas/farmacocinética , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Quinolonas/síntesis química , Quinolonas/farmacocinética , Ratas Wistar , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto
17.
J Exp Med ; 216(2): 450-465, 2019 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-30642944

RESUMEN

Lung squamous cell carcinoma (LSCC) and adenocarcinoma (LADC) are the most common lung cancer subtypes. Molecular targeted treatments have improved LADC patient survival but are largely ineffective in LSCC. The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC. Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice. KF LSCC tumors recapitulated human LSCC resistance to cisplatin-based chemotherapy, and we identified LUBAC-mediated NF-κB signaling as a determinant of chemotherapy resistance in human and mouse. Inhibition of NF-κB activation using TAK1 or LUBAC inhibitors resensitized LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.


Asunto(s)
Carcinoma de Células Escamosas/enzimología , Resistencia a Antineoplásicos , Neoplasias Pulmonares/enzimología , Complejos Multienzimáticos/metabolismo , Ubiquitinación , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/enzimología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Cisplatino/farmacología , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Complejos Multienzimáticos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo
18.
ACS Appl Mater Interfaces ; 10(2): 1976-1986, 2018 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-29257666

RESUMEN

Visible light photocatalysis by TiO2 requires efficient doping of other elements with red-shifted band edge to the visible region. However, preparation of such TiO2 with tunable doping is challenging. Here we report a method of making nitrogen (N) and fluorine (F) codoped TiO2 nanoparticle with tunable doping between 1 and 7 at. %. The preparation of N, F codoped TiO2 nanoparticle involves reaction of colloidal TiO2 nanorods with an ammonium fluoride-urea mixture at 300 °C, and the extent of N/F doping is tuned by varying the amount of ammonium fluoride-urea and the reaction time. Resultant colloidal N, F codoped TiO2 nanoparticles show doping dependent shifting of the band edge from the UV to near-IR region, visible light induced generation of reactive oxygen species (ROS), and visible light photodegradation of bisphenol A. A colloidal form of doped TiO2 nanoparticle offers labeling of cells, visible light induced ROS generation inside a cell, and successive cell death. This work shows the potential advantage of anisotropic nanoparticle precursor for tunable doping and colloidal form of N, F codoped TiO2 nanoparticle as a visible light photocatalyst.


Asunto(s)
Nanopartículas , Catálisis , Muerte Celular , Flúor , Luz , Nitrógeno , Titanio
19.
ChemMedChem ; 13(22): 2427-2436, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30222248

RESUMEN

Folic acid (FA), vitamin B9 , is a good receptor of drugs triggering cellular uptake via endocytosis. FA is sparingly soluble in water. Herein, a new approach for the formation of FA hydrogel by the hydrolysis of glucono-δ-lactone in PBS buffer under physiological conditions has been reported. The gel has a fibrillar network morphology attributable to intermolecular H-bonding and π-stacking interactions. The thixotropic property of the gel is used for the encapsulation of both hydrophilic [doxorubicin (DOX)] and hydrophobic [camptothecin (CPT)] drugs. The loading of DOX and CPT into the gel is attributed to the H-bonding interaction between FA and drugs. The release of DOX is sustainable at pH 4 and 7, and the Peppas model indicates that at pH 7 the diffusion of the drug is Fickian but it is non-Fickian at pH 4. The release of CPT is monitored by fluorescence spectroscopy, which also corroborates the combined release of both drugs. The metylthiazolyldiphenyltetrazolium bromide assay of FA hydrogel demonstrates nontoxic behavior and that the cytotoxicity of the DOX-loaded FA hydrogel is higher than that of pure DOX, with a minimal effect on normal cells.


Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/química , Ácido Fólico/química , Hidrogeles/química , Animales , Antineoplásicos/química , Células CHO , Camptotecina/química , Cricetulus , Difusión , Doxorrubicina/química , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Ácido Fólico/toxicidad , Gluconatos/química , Gluconatos/toxicidad , Células HeLa , Humanos , Hidrogeles/toxicidad , Concentración de Iones de Hidrógeno , Hidrólisis , Interacciones Hidrofóbicas e Hidrofílicas , Lactonas/química , Ratones
20.
Protein Eng Des Sel ; 20(1): 1-5, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17218337

RESUMEN

Transcription activator protein C of bacteriophage Mu activates transcription of the late genes, including mom, during the lytic cycle of the phage. C binding to its site leads to the alteration in DNA topology of the promoter elements resulting in RNA polymerase (RNAP) recruitment. At the next step, the transactivator enhances promoter clearance of RNAP from P(mom). The C protein binds DNA with a very high affinity using a carboxyl-terminal helix turn helix (HTH) motif which has similarity with the HTH from paired domain of Drosophila prd protein. Previous studies established that the protein is dimeric in free and DNA bound forms. We describe now the unique dimerization interface of the protein. Two heptad repeats of hydrophobic amino acids found in the protein were considered to be the candidates for dimerization region. Site-directed mutational analysis revealed that the amino-terminal coiled coil region is not the dimerization determinant. In contrast, similar mutagenesis studies indicated a role for the leucine zipper motif, located in the middle region of the protein, in dimerization. Mixed oligomerization assays confirmed the importance of leucine zipper in C dimer formation establishing the presence of an uncommon zipper-HTH domain in the transactivator.


Asunto(s)
Bacteriófago mu/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/química , Proteínas Virales/química , Secuencia de Aminoácidos , Bacteriófago mu/metabolismo , Dimerización , Secuencias Hélice-Giro-Hélice , Leucina Zippers , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida
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