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1.
ACS Med Chem Lett ; 15(6): 791-797, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38894895

RESUMEN

Bfl-1 is overexpressed in both hematological and solid tumors; therefore, inhibitors of Bfl-1 are highly desirable. A DNA-encoded chemical library (DEL) screen against Bfl-1 identified the first known reversible covalent small-molecule ligand for Bfl-1. The binding was validated through biophysical and biochemical techniques, which confirmed the reversible covalent mechanism of action and pointed to binding through Cys55. This represented the first identification of a cyano-acrylamide reversible covalent compound from a DEL screen and highlights further opportunities for covalent drug discovery through DEL screening. A 10-fold improvement in potency was achieved through a systematic SAR exploration of the hit. The more potent analogue compound 13 was successfully cocrystallized in Bfl-1, revealing the binding mode and providing further evidence of a covalent interaction with Cys55.

2.
MethodsX ; 12: 102562, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38292308

RESUMEN

Stalk lodging (structural failure crops prior to harvest) significantly reduces annual yields of vital grain crops. The lack of standardized, high throughput phenotyping methods capable of quantifying biomechanical plant traits prevents comprehensive understanding of the genetic architecture of stalk lodging resistance. A phenotyping pipeline developed to enable higher throughput biomechanical measurements of plant traits related to stalk lodging is presented. The methods were developed using principles from the fields of engineering mechanics and metrology and they enable retention of plant-specific data instead of averaging data across plots as is typical in most phenotyping studies. This pipeline was specifically designed to be implemented in large experimental studies and has been used to phenotype over 40,000 maize stalks. The pipeline includes both lab- and field-based phenotyping methodologies and enables the collection of metadata. Best practices learned by implementing this pipeline over the past three years are presented. The specific instruments (including model numbers and manufacturers) that work well for these methods are presented, however comparable instruments may be used in conjunction with these methods as seen fit.•Efficient methods to measure biomechanical traits and record metadata related to stalk lodging.•Can be used in studies with large sample sizes (i.e., > 1,000).

3.
Chem Sci ; 14(26): 7136-7146, 2023 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-37416723

RESUMEN

Plant homeodomain fingers (PHD-fingers) are a family of reader domains that can recruit epigenetic proteins to specific histone modification sites. Many PHD-fingers recognise methylated lysines on histone tails and play crucial roles in transcriptional regulation, with their dysregulation linked to various human diseases. Despite their biological importance, chemical inhibitors for targeting PHD-fingers are very limited. Here we report a potent and selective de novo cyclic peptide inhibitor (OC9) targeting the Nε-trimethyllysine-binding PHD-fingers of the KDM7 histone demethylases, developed using mRNA display. OC9 disrupts PHD-finger interaction with histone H3K4me3 by engaging the Nε-methyllysine-binding aromatic cage through a valine, revealing a new non-lysine recognition motif for the PHD-fingers that does not require cation-π interaction. PHD-finger inhibition by OC9 impacted JmjC-domain mediated demethylase activity at H3K9me2, leading to inhibition of KDM7B (PHF8) but stimulation of KDM7A (KIAA1718), representing a new approach for selective allosteric modulation of demethylase activity. Chemoproteomic analysis showed selective engagement of OC9 with KDM7s in T cell lymphoblastic lymphoma SUP T1 cells. Our results highlight the utility of mRNA-display derived cyclic peptides for targeting challenging epigenetic reader proteins to probe their biology, and the broader potential of this approach for targeting protein-protein interactions.

4.
Chem Sci ; 14(25): 7057-7067, 2023 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-37389247

RESUMEN

Understanding allosteric regulation in biomolecules is of great interest to pharmaceutical research and computational methods emerged during the last decades to characterize allosteric coupling. However, the prediction of allosteric sites in a protein structure remains a challenging task. Here, we integrate local binding site information, coevolutionary information, and information on dynamic allostery into a structure-based three-parameter model to identify potentially hidden allosteric sites in ensembles of protein structures with orthosteric ligands. When tested on five allosteric proteins (LFA-1, p38-α, GR, MAT2A, and BCKDK), the model successfully ranked all known allosteric pockets in the top three positions. Finally, we identified a novel druggable site in MAT2A confirmed by X-ray crystallography and SPR and a hitherto unknown druggable allosteric site in BCKDK validated by biochemical and X-ray crystallography analyses. Our model can be applied in drug discovery to identify allosteric pockets.

5.
J Med Chem ; 66(13): 8782-8807, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37343272

RESUMEN

Recent clinical reports have highlighted the need for wild-type (WT) and mutant dual inhibitors of c-MET kinase for the treatment of cancer. We report herein a novel chemical series of ATP competitive type-III inhibitors of WT and D1228V mutant c-MET. Using a combination of structure-based drug design and computational analyses, ligand 2 was optimized to a highly selective chemical series with nanomolar activities in biochemical and cellular settings. Representatives of the series demonstrate excellent pharmacokinetic profiles in rat in vivo studies with promising free-brain exposures, paving the way for the design of brain permeable drugs for the treatment of c-MET driven cancers.


Asunto(s)
Antineoplásicos , Neoplasias , Ratas , Animales , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-met , Diseño de Fármacos , Adenosina Trifosfato , Antineoplásicos/farmacología
6.
J Chem Phys ; 158(15)2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37093996

RESUMEN

Poly(vinyl alcohol) (PVA) has ice binding and ice nucleating properties. Here, we explore the dependence of the molecular size of PVA on its ice nucleation activity. For this purpose, we studied ice nucleation in aqueous solutions of PVA samples with molar masses ranging from 370 to 145 000 g mol-1, with a particular focus on oligomer samples with low molar mass. The experiments employed a novel microfluidic setup that is a follow-up on the previous WeIzmann Supercooled Droplets Observation on a Microarray (WISDOM) design by Reicher et al. The modified setup introduced and characterized here, termed nanoliter Bielefeld Ice Nucleation ARraY (nanoBINARY), uses droplet microfluidics with droplets (96 ± 4) µm in diameter and a fluorinated continuous oil phase and surfactant. A comparison of homogeneous and heterogeneous ice nucleation data obtained with nanoBINARY to those obtained with WISDOM shows very good agreement, underpinning its ability to study low-temperature ice nucleators as well as homogeneous ice nucleation due to the low background of impurities. The experiments on aqueous PVA solutions revealed that the ice nucleation activity of shorter PVA chains strongly decreases with a decrease in molar mass. While the cumulative number of ice nucleating sites per mass nm of polymers with different molar masses is the same, it becomes smaller for oligomers and completely vanishes for dimer and monomer representatives such as 1,3-butanediol, propan-2-ol, and ethanol, most likely because these molecules become too small to effectively stabilize the critical ice embryo. Overall, our results are consistent with PVA polymers and oligomers acting as heterogeneous ice nucleators.

7.
Plant Methods ; 19(1): 3, 2023 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-36624506

RESUMEN

This study presents a methodology for a high-throughput digitization and quantification process of plant cell walls characterization, including the automated development of two-dimensional finite element models. Custom algorithms based on machine learning can also analyze the cellular microstructure for phenotypes such as cell size, cell wall curvature, and cell wall orientation. To demonstrate the utility of these models, a series of compound microscope images of both herbaceous and woody representatives were observed and processed. In addition, parametric analyses were performed on the resulting finite element models. Sensitivity analyses of the structural stiffness of the resulting tissue based on the cell wall elastic modulus and the cell wall thickness; demonstrated that the cell wall thickness has a three-fold larger impact of tissue stiffness than cell wall elastic modulus.

8.
RSC Med Chem ; 13(9): 1052-1057, 2022 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-36324499

RESUMEN

Fragment based drug discovery is a critical part of the lead generation toolbox and relies heavily on a readily available, high quality fragment library. Over years of use, the AstraZeneca fragment set had become partially depleted and instances of compound deterioration had been found. It was recognised that a redevelopment was required. This provided an opportunity to evolve our screening sets strategy, whilst ensuring that the quality of the fragment set met the robust requirements of fragment screening campaigns. In this communication we share the strategy employed, in particular highlighting two aspects of our approach that we believe others in the community would benefit from, namely that; (i) fragments were selected with input from Medicinal Chemists at an early stage, and (ii) the library was arranged in a layered format to ensure maximum flexibility on a per target basis.

9.
Bioorg Med Chem Lett ; 75: 128948, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-35987508

RESUMEN

The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.


Asunto(s)
Antineoplásicos , Proteínas Proto-Oncogénicas c-met , Antineoplásicos/farmacología , Línea Celular Tumoral , ADN , Inhibidores de Proteínas Quinasas/química , Bibliotecas de Moléculas Pequeñas/química
10.
J Am Soc Mass Spectrom ; 33(7): 1168-1175, 2022 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-35675480

RESUMEN

Liquid extraction surface analysis (LESA) coupled to native mass spectrometry (MS) presents unique analytical opportunities due to its sensitivity, speed, and automation. Here, we examine whether this tool can be used to quantitatively probe protein-ligand interactions through calculation of equilibrium dissociation constants (Kd values). We performed native LESA MS analyses for a well-characterized system comprising bovine carbonic anhydrase II and the ligands chlorothiazide, dansylamide, and sulfanilamide, and compared the results with those obtained from direct infusion mass spectrometry and surface plasmon resonance measurements. Two LESA approaches were considered: In one approach, the protein and ligand were premixed in solution before being deposited and dried onto a solid substrate for LESA sampling, and in the second, the protein alone was dried onto the substrate and the ligand was included in the LESA sampling solvent. Good agreement was found between the Kd values derived from direct infusion MS and LESA MS when the protein and ligand were premixed; however, Kd values determined from LESA MS measurements where the ligand was in the sampling solvent were inconsistent. Our results suggest that LESA MS is a suitable tool for quantitative analysis of protein-ligand interactions when the dried sample comprises both protein and ligand.


Asunto(s)
Inhibidores de Anhidrasa Carbónica , Extracción Líquido-Líquido , Animales , Inhibidores de Anhidrasa Carbónica/análisis , Bovinos , Ligandos , Extracción Líquido-Líquido/métodos , Espectrometría de Masas/métodos , Proteínas/química , Solventes
11.
Plant Methods ; 18(1): 56, 2022 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-35477510

RESUMEN

BACKGROUND: Stalk lodging (breaking of agricultural plant stalks prior to harvest) is a multi-billion dollar a year problem. Stalk lodging occurs when high winds induce bending moments in the stalk which exceed the bending strength of the plant. Previous biomechanical models of plant stalks have investigated the effect of cross-sectional morphology on stalk lodging resistance (e.g., diameter and rind thickness). However, it is unclear if the location of stalk failure along the length of stem is determined by morphological or compositional factors. It is also unclear if the crops are structurally optimized, i.e., if the plants allocate structural biomass to create uniform and minimal bending stresses in the plant tissues. The purpose of this paper is twofold: (1) to investigate the relationship between bending stress and failure location of maize stalks, and (2) to investigate the potential of phenotyping for internode-level bending stresses to assess lodging resistance. RESULTS: 868 maize specimens representing 16 maize hybrids were successfully tested in bending to failure. Internode morphology was measured, and bending stresses were calculated. It was found that bending stress is highly and positively associated with failure location. A user-friendly computational tool is presented to help plant breeders in phenotyping for internode-level bending stress. Phenotyping for internode-level bending stresses could potentially be used to breed for more biomechanically optimal stalks that are resistant to stalk lodging. CONCLUSIONS: Internode-level bending stress plays a potentially critical role in the structural integrity of plant stems. Equations and tools provided herein enable researchers to account for this phenotype, which has the potential to increase the bending strength of plants without increasing overall structural biomass.

12.
Science ; 375(6582): 770-774, 2022 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-35175822

RESUMEN

Lizard tail autotomy is an antipredator strategy consisting of sturdy attachment at regular times but quick detachment during need. We propose a biomimetic fracture model of lizard tail autotomy using multiscale hierarchical structures. The structures consist of uniformly distributed micropillars with nanoporous tops, which recapitulate the high-density mushroom-shaped microstructures found on the lizard tail's muscle fracture plane. The biomimetic experiments showed adhesion enhancement when combining nanoporous interfacial surfaces with flexible micropillars in tensile and peel modes. The fracture modeling identified micro- and nanostructure-based toughening mechanisms as the critical factor. Under wet conditions, capillarity-assisted energy dissipation pertaining to liquid-filled microgaps and nanopores further increased the adhesion performance. This research presents insights on lizard tail autotomy and provides new biomimetic ideas to solve adhesion problems.


Asunto(s)
Conducta Animal , Biomimética , Lagartos/fisiología , Modelos Biológicos , Cola (estructura animal)/fisiología , Adhesividad , Animales , Fenómenos Biofísicos , Dimetilpolisiloxanos , Lagartos/anatomía & histología , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Regeneración , Cola (estructura animal)/anatomía & histología
13.
Sci Rep ; 12(1): 720, 2022 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-35031627

RESUMEN

The maize (Zea mays) stem is a biological structure that must balance both biotic and structural load bearing duties. These competing requirements are particularly relevant in the design of new bioenergy crops. Although increased stem digestibility is typically associated with a lower structural strength and higher propensity for lodging, with the right balance between structural and biological activities it may be possible to design crops that are high-yielding and have digestible biomass. This study investigates the hypothesis that geometric factors are much more influential in determining structural strength than tissue properties. To study these influences, both physical and in silico experiments were used. First, maize stems were tested in three-point bending. Specimen-specific finite element models were created based on x-ray computed tomography scans. Models were validated by comparison with experimental data. Sensitivity analyses were used to assess the influence of structural parameters such as geometric and material properties. As hypothesized, geometry was found to have a much stronger influence on structural stability than material properties. This information reinforces the notion that deficiencies in tissue strength could be offset by manipulation of stalk morphology, thus allowing the creation of stalks which are both resilient and digestible.


Asunto(s)
Fenómenos Biomecánicos , Productos Agrícolas , Zea mays/anatomía & histología , Zea mays/fisiología , Biocombustibles , Biomasa , Simulación por Computador , Docilidad , Resistencia a la Tracción , Tomografía Computarizada por Rayos X
14.
Plant Methods ; 18(1): 1, 2022 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-34983578

RESUMEN

BACKGROUND: Stalk lodging (mechanical failure of plant stems during windstorms) leads to global yield losses in cereal crops estimated to range from 5% to 25% annually. The cross-sectional morphology of plant stalks is a key determinant of stalk lodging resistance. However, previously developed techniques for quantifying cross-sectional morphology of plant stalks are relatively low-throughput, expensive and often require specialized equipment and expertise. There is need for a simple and cost-effective technique to quantify plant traits related to stalk lodging resistance in a high-throughput manner. RESULTS: A new phenotyping methodology was developed and applied to a range of plant samples including, maize (Zea mays), sorghum (Sorghum bicolor), wheat (Triticum aestivum), poison hemlock (Conium maculatum), and Arabidopsis (Arabis thaliana). The major diameter, minor diameter, rind thickness and number of vascular bundles were quantified for each of these plant types. Linear correlation analyses demonstrated strong agreement between the newly developed method and more time-consuming manual techniques (R2 > 0.9). In addition, the new method was used to generate several specimen-specific finite element models of plant stalks. All the models compiled without issue and were successfully imported into finite element software for analysis. All the models demonstrated reasonable and stable solutions when subjected to realistic applied loads. CONCLUSIONS: A rapid, low-cost, and user-friendly phenotyping methodology was developed to quantify two-dimensional plant cross-sections. The methodology offers reduced sample preparation time and cost as compared to previously developed techniques. The new methodology employs a stereoscope and a semi-automated image processing algorithm. The algorithm can be used to produce specimen-specific, dimensionally accurate computational models (including finite element models) of plant stalks.

15.
Bioinspir Biomim ; 17(3)2022 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-35073538

RESUMEN

Biological soft interfaces often exhibit complex microscale interlocking geometries to ensure sturdy and flexible connections. If needed, the interlocking can rapidly be released on demand leading to an abrupt decrease of interfacial adhesion. Here, inspired by lizard tail autotomy where such apparently tunable interfacial fracture behavior can be observed, we hypothesized an interlocking mechanism between the tail and body based on the muscle-actuated mushroom-shaped microinterlocks along the fracture planes. To mimic the fracture behavior of the lizard tail, we developed a soft bilayer patch that consisted of a dense array of soft hemispherical microstructures in the upper layer acting as mechanical interlocks with the counter body part. The bottom control layer contained a microchannel that allowed to deflect the upper layer when applying the negative pressure, thus mimicking muscle contraction. In the microinterlocked condition, the biomimetic tail demonstrated a 2.7-fold and a three-fold increase in adhesion strength and toughness, respectively, compared to the pneumatically released microinterlocks. Furthermore, as per the computational analysis, the subsurface microchannel in the control layer enabled augmented adhesion by rendering the interface more compliant as a dissipative matrix, decreasing contact opening and strain energy dissipation by 50%. The contrasting features between the microinterlocked and released cases demonstrated a highly tunable adhesion of our biomimetic soft patch. The potential applications of our study are expected in soft robotics and prosthetics.


Asunto(s)
Lagartos , Animales , Biomimética , Lagartos/fisiología , Contracción Muscular , Cola (estructura animal)/fisiología
16.
Ultrasound ; 30(4): 264-272, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36969536

RESUMEN

Introduction: Urinary tract obstruction (UTO) is a common clinical problem of which there are many potential causes. The aim of this feature article is to explore the role of ultrasound in diagnosing UTO, during guided interventional procedures and the potential procedural complications.Topic description and discussion: Ultrasound is an integral imaging modality throughout the management pathway of a patient with UTO and is often utilised as a first-line test in diagnosis and treatment. Percutaneous nephrostomy is an interventional technique, usually performed by radiologists or interventional sonographers, as either a short- or long-term management strategy. It can either be used in isolation or to gain access to the renal collecting system prior to more complex interventional or surgical techniques. Ultrasound-guided interventional techniques to relieve UTO can be employed in a number of clinical scenarios each with their own indications, contraindications and complications. Conclusion: Ultrasound plays a unique role in the planning and active stages of intervention with the provision of dynamic imaging which is crucial for providing safe and effective patient management.

17.
Commun Biol ; 4(1): 1273, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34754068

RESUMEN

Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and oncology drug target that regulates gene transcription through binding to acetylated chromatin via bromodomains. Phosphorylation by casein kinase II (CK2) regulates BRD4 function, is necessary for active transcription and is involved in resistance to BRD4 drug inhibition in triple-negative breast cancer. Here, we provide the first biophysical analysis of BRD4 phospho-regulation. Using integrative structural biology, we show that phosphorylation by CK2 modulates the dimerization of human BRD4. We identify two conserved regions, a coiled-coil motif and the Basic-residue enriched Interaction Domain (BID), essential for the BRD4 structural rearrangement, which we term the phosphorylation-dependent dimerization domain (PDD). Finally, we demonstrate that bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Our results enable the proposal of a model for BRD4 activation critical for the characterization of its protein-protein interaction network and for the development of more specific therapeutics.


Asunto(s)
Proteínas de Ciclo Celular/genética , Regulación de la Expresión Génica , Factores de Transcripción/genética , Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Proteínas de Ciclo Celular/metabolismo , Humanos , Fosforilación , Factores de Transcripción/metabolismo
18.
Plant Methods ; 17(1): 101, 2021 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-34620195

RESUMEN

BACKGROUND: Flexural three-point bending tests are useful for characterizing the mechanical properties of plant stems. These tests can be performed with minimal sample preparation, thus allowing tests to be performed relatively quickly. The best-practice for such tests involves long spans with supports and load placed at nodes. This approach typically provides only one flexural stiffness measurement per specimen. However, by combining flexural tests with analytic equations, it is possible to solve for the mechanical characteristics of individual stem segments. RESULTS: A method is presented for using flexural tests to obtain estimates of flexural stiffness of individual segments. This method pairs physical test data with analytic models to obtain a system of equations. The solution of this system of equations provides values of flexural stiffness for individual stalk segments. Uncertainty in the solved values for flexural stiffness were found to be strongly dependent upon measurement errors. Row-wise scaling of the system of equations reduced the influence of measurement error. Of many possible test combinations, the most advantageous set of tests for performing these measurements were identified. Relationships between measurement uncertainty and solution uncertainty were provided for two different testing methods. CONCLUSIONS: The methods presented in this paper can be used to measure the axial variation in flexural stiffness of plant stem segments. However, care must be taken to account for the influence of measurement error as the individual segment method amplifies measurement error. An alternative method involving aggregate flexural stiffness values does not amplify measurement error, but provides lower spatial resolution.

19.
Front Plant Sci ; 12: 617880, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34489984

RESUMEN

The biomechanical role of the clasping leaf sheath in stalk lodging events has been historically understudied. Results from this study indicate that in some instances the leaf sheath plays an even larger role in reinforcing wheat against stalk lodging than the stem itself. Interestingly, it appears the leaf sheath does not resist bending loads by merely adding more material to the stalk (i.e., increasing the effective diameter). The radial preload of the leaf sheath on the stem, the friction between the sheath and the stem and several other complex biomechanical factors may contribute to increasing the stalk bending strength and stalk flexural rigidity of wheat. Results demonstrated that removal of the leaf sheath induces alternate failure patterns in wheat stalks. In summary the biomechanical role of the leaf sheath is complex and has yet to be fully elucidated. Many future studies are needed to develop high throughput phenotyping methodologies and to determine the genetic underpinnings of the clasping leaf sheath and its relation to stalk lodging resistance. Research in this area is expected to improve the lodging resistance of wheat.

20.
J Med Chem ; 64(10): 6814-6826, 2021 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-33900758

RESUMEN

MAT2a is a methionine adenosyltransferase that synthesizes the essential metabolite S-adenosylmethionine (SAM) from methionine and ATP. Tumors bearing the co-deletion of p16 and MTAP genes have been shown to be sensitive to MAT2a inhibition, making it an attractive target for treatment of MTAP-deleted cancers. A fragment-based lead generation campaign identified weak but efficient hits binding in a known allosteric site. By use of structure-guided design and systematic SAR exploration, the hits were elaborated through a merging and growing strategy into an arylquinazolinone series of potent MAT2a inhibitors. The selected in vivo tool compound 28 reduced SAM-dependent methylation events in cells and inhibited proliferation of MTAP-null cells in vitro. In vivo studies showed that 28 was able to induce antitumor response in an MTAP knockout HCT116 xenograft model.


Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/química , Metionina Adenosiltransferasa/antagonistas & inhibidores , Sitio Alostérico , Animales , Proliferación Celular , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Técnicas de Inactivación de Genes , Células HCT116 , Semivida , Humanos , Metionina Adenosiltransferasa/genética , Metionina Adenosiltransferasa/metabolismo , Ratones , Simulación de Dinámica Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacología , Quinazolinas/uso terapéutico , Ratas , S-Adenosilmetionina/metabolismo , Relación Estructura-Actividad , Trasplante Heterólogo
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