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High energy density lithium-ion batteries (LIBs) adopting high-nickel layered oxide cathodes and silicon-based composite anodes always suffer from unsatisfied cycle life and poor safety performance, especially at elevated temperatures. Electrode /electrolyte interphase regulation by functional additives is one of the most economic and efficacious strategies to overcome this shortcoming. Herein, cyano-groups (-CN) are introduced into lithium fluorinated phosphate to synthesize a novel multifunctional additive of lithium tetrafluoro (1,2-dihydroxyethane-1,1,2,2-tetracarbonitrile) phosphate (LiTFTCP), which endows high nickel LiNi0.8 Co0.1 Mn0.1 O2 /SiOx -graphite composite full cell with an ultrahigh cycle life and superior safety characteristics, by adding only 0.5â wt % LiTFTCP into a LiPF6 -carbonate baseline electrolyte. It is revealed that LiTFTCP additive effectively suppresses the HF generation and facilitates the formation of a robust and heat-resistant cyano-enriched CEI layer as well as a stable LiF-enriched SEI layer. The favorable SEI/CEI layers greatly lessen the electrode degradation, electrolyte consumption, thermal-induced gassing and total heat-releasing. This work illuminates the importance of additive molecular engineering and interphase regulation in simultaneously promoting the cycling and thermal safety of LIBs with high-nickel NCMxyz cathode and silicon-based composite anode.
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Traditional lithium salts are difficult to meet practical application demand of lithium metal batteries (LMBs) under high voltages and temperatures. LiPF6, as the most commonly used lithium salt, still suffers from notorious moisture sensitivity and inferior thermal stability under those conditions. Here, we synthesize a lithium salt of lithium perfluoropinacolatoborate (LiFPB) comprising highly-fluorinated and borate functional groups to address the above issues. It is demonstrated that the LiFPB shows superior thermal and electrochemical stability without any HF generation under high temperatures and voltages. In addition, the LiFPB can form a protective outer-organic and inner-inorganic rich cathode electrolyte interphase on LiCoO2 (LCO) surface. Simultaneously, the FPB- anions tend to integrate into lithium ion solvation structure to form a favorable fast-ion conductive LiBxOy based solid electrolyte interphase on lithium (Li) anode. All these fantastic features of LiFPB endow LCO (1.9â mAh cm-2)/Li metal cells excellent cycling under both high voltages and temperatures (e.g., 80 % capacity retention after 260â cycles at 60 °C and 4.45â V), and even at an extremely elevated temperature of 100 °C. This work emphasizes the important role of salt anions in determining the electrochemical performance of LMBs at both high temperature and voltage conditions.
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Rechargeable lithium metal (Li0) batteries (RLMBs) are considered attractive for improving Li-ion batteries. Lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) has been extensively used as a conducting salt for RLMBs due to its advantageous stability and innocuity. However, LiTFSI-based electrolytes are corrosive towards aluminium (Al0) current collectors at low potentials (>3.8 V versus Li/Li+), thereby excluding their application in 4-V-class RLMBs. Herein, we report on a non-corrosive sulfonimide salt, lithium (difluoromethanesulfonyl)(trifluoromethanesulfonyl)imide (LiDFTFSI), that remarkably suppresses the anodic dissolution of the Al0 current collector at high potentials (>4.2 V versus Li/Li+) and significantly improves the cycling performance of Li(Ni1/3Mn1/3Co1/3)O2 (NMC111) cells. In addition, this sulfonimide salt results in the growth of an advantageous solid electrolyte interphase on the Li0 electrode. The replacement of either LiTFSI or LiPF6 with LiDFTFSI endows a Li0||NMC111 cell with superior cycling stability and capacity retention (87% at cycle 200), demonstrating the decisive role of the salt anion in dictating the electrochemical performance of RLMBs.
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Lithium difluoro(oxalato) borate (LiDFOB) has been widely investigated in lithium-ion batteries (LIBs) owing to its advantageous thermal stability and excellent aluminum passivation property. However, LiDFOB tends to suffer from severe decomposition and generate a lot of gas species (e.g., CO2 ). Herein, a novel cyano-functionalized lithium borate salt, namely lithium difluoro(1,2-dihydroxyethane-1,1,2,2-tetracarbonitrile) borate (LiDFTCB), is innovatively synthesized as a highly oxidative-resistant salt to alleviate above dilemma. It is revealed that the LiDFTCB-based electrolyte enables LiCoO2 /graphite cells with superior capacity retention at both room and elevated temperatures (e.g., 80 % after 600â cycles) with barely any CO2 gas evolution. Systematic studies reveal that LiDFTCB tends to form thin and robust interfacial layers at both electrodes. This work emphasizes the crucial role of cyano-functionalized anions in improving cycle lifespan and safety of practical LIBs.
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Polymer electrolytes (PEs) with excellent flexibility, processability, and good contact with lithium metal (Li°) anodes have attracted substantial attention in both academic and industrial settings. However, conventional poly(ethylene oxide) (PEO)-based PEs suffer from a low lithium-ion transference number (TLi+), leading to a notorious concentration gradient and internal cell polarization. Here, we report two kinds of highly lithium-ion conductive and solvent-free PEs using the benzene-based lithium salts, lithium (benzenesulfonyl)(trifluoromethanesulfonyl)imide (LiBTFSI) and lithium (2,4,6-triisopropylbenzenesulfonyl)(trifluoromethanesulfonyl)imide (LiTPBTFSI), which show significantly improved TLi+ and selective lithium-ion conductivity. Using molecular dynamics simulations, we pinpoint the strong π-π stacking interaction between pairs of benzene-based anions as the cause of this improvement. In addition, we show that Li°â¥Li° and Li°â¥LiFePO4 cells with the LiBTFSI/PEO electrolytes present enhanced cycling performance. By considering π-π stacking interactions as a new molecular-level design route of salts for electrolyte, this work provides an efficient and facile novel strategy for attaining highly selective lithium-ion conductive PEs.
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Pollen development is a key process for the sexual reproduction of angiosperms. The Golgi plays a critical role in pollen development via the synthesis and transport of cell wall materials. However, little is known about the molecular mechanisms underlying the maintenance of Golgi integrity in plants. In Arabidopsis thaliana, syntaxin of plants (SYP) 3 family proteins SYP31 and SYP32 are the only two Golgi-localized Qa-soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) with unknown endogenous functions. Here, we demonstrate the roles of SYP31 and SYP32 in modulating Golgi morphology and pollen development. Two independent lines of syp31/+ syp32/+ double mutants were male gametophytic lethal; the zero transmission rate of syp31 syp32 mutations was restored to largely normal levels by pSYP32:SYP32 but not pSYP32:SYP31 transgenes, indicating their functional differences in pollen development. The initial arrest of syp31 syp32 pollen occurred during the transition from the microspore to the bicellular stage, where cell plate formation in pollen mitosis I (PMI) and deposition of intine were abnormal. In syp31 syp32 pollen, the number and length of Golgi cisterna were significantly reduced, accompanied by many surrounding vesicles, which could be largely attributed to defects in anterograde and retrograde trafficking routes. SYP31 and SYP32 directly interacted with COG3, a subunit of the conserved oligomeric Golgi (COG) complex and were responsible for its Golgi localization, providing an underlying mechanism for SYP31/32 function in intra-Golgi trafficking. We propose that SYP31 and SYP32 play partially redundant roles in pollen development by modulating protein trafficking and Golgi structure.
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Proteínas de Arabidopsis , Arabidopsis , Complexo de Golgi , Pólen , Proteínas Qa-SNARE , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Complexo de Golgi/metabolismo , Pólen/genética , Pólen/crescimento & desenvolvimento , Transporte Proteico , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismoRESUMO
Rechargeable magnesium batteries (RMBs) have been considered as one of the most viable battery chemistries amongst the "post" lithium-ion battery (LIB) technologies owing to their high volumetric capacity and the natural abundance of their key elements. The fundamental properties of Mg-ion conducting electrolytes are of essence to regulate the overall performance of RMBs. In this Review, the basic electrochemistry of Mg-ion conducting electrolytes batteries is discussed and compared to that of the Li-ion conducting electrolytes, and a comprehensive overview of the development of different Mg-ion conducting electrolytes is provided. In addition, the remaining challenges and possible solutions for future research are intensively discussed. The present work is expected to give an impetus to inspire the discovery of key electrolytes and thereby improve the electrochemical performances of RMBs and other related emerging battery technologies.
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The streptavidin mass shift (SMaSh) assay is a robust and fast approach for quantifying target protein occupancy by a covalent inhibitor or ligand. It exploits the biotin-streptavidin bond using the Simple Western platform. One measurement on a single sample determines both total and occupied target protein simultaneously and is, therefore, self-normalizing. The approach works in diverse and complex biological matrices and, with no need for matched vehicle-treated controls, readily applies to tissues from animal pharmacology models. Assessing occupancy is critical in the development of targeted covalent drugs. We demonstrate its use by characterizing and validating a variety of chemical probes for Bruton's tyrosine kinase (BTK, UniprotKB Q10607) and mitogen-activated protein kinase (ERK1/2/MAPK1/2, UniprotKB P28482 and P27361) and determining target engagement of covalent inhibitors for both targets and off-target engagement for ERK. We demonstrated that it works in cell lysates, tissues, and human peripheral blood mononuclear cells. The SMaSh assay is superior to traditional methods and broadly useful as a tool in assessing covalent biological probes or targeted covalent inhibitors.
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Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Bioensaio/métodos , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Estreptavidina/química , Linhagem Celular Tumoral , Humanos , Leucócitos Mononucleares/enzimologia , Estrutura Molecular , Estreptavidina/metabolismo , Relação Estrutura-AtividadeRESUMO
SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) complex formation is necessary for intracellular membrane fusion and thus has a key role in processes such as secretion. However, little is known about the regulatory factors that bind to Qa-SNAREs, which are also known as syntaxins (SYPs) in plants. Here, we characterized Arabidopsis (Arabidopsis thaliana) Tomosyn protein (AtTMS) and demonstrated that it is a conserved regulator of SYPs in plants. AtTMS binds strongly via its R-SNARE motif-containing C terminus to the Qa domain of PM-resident, pollen-expressed SYP1s (SYP111, SYP124, SYP125, SYP131, and SYP132), which were narrowed down from 12 SYPs. AtTMS is highly expressed in pollen from the bicellular stage onwards, and overexpression of AtTMS under the control of the UBIQUITIN10, MSP1, or LAT52 promoter all resulted in defective pollen after the microspore stage in which secretion was inhibited, leading to the failure of intine deposition and cell plate formation during pollen mitosis I. In tobacco (Nicotiana benthamiana) leaf epidermal cells, overexpression of AtTMS inhibited the secretion of secreted GFP. The defects were rescued by mCherry-tagged SYP124, SYP125, SYP131, or SYP132. In vivo, SYP132 partially rescued the pMSP1:AtTMS phenotype. In addition, AtTMS, lacking a transmembrane domain, was recruited to the plasma membrane by SYP124, SYP125, SYP131, and SYP132 and competed with Vesicle-Associated Membrane Protein721/722 for binding to, for example, SYP132. Together, our results demonstrated that AtTMS might serve as a negative regulator of secretion, whereby active secretion might be fine-tuned during pollen development.
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Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas SNARE/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Transporte Biológico , Membrana Celular/metabolismo , Expressão Gênica , Fusão de Membrana , Pólen/genética , Pólen/crescimento & desenvolvimento , Pólen/fisiologia , Ligação Proteica , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Proteínas SNARE/genética , Vesículas Secretórias/metabolismo , Nicotiana/genética , Nicotiana/fisiologiaRESUMO
Suppressing the mobility of anionic species in polymer electrolytes (PEs) is essential for mitigating the concentration gradient and internal cell polarization, and thereby improving the stability and cycle life of rechargeable alkali metal batteries. Now, an ether-functionalized anion (EFA) is used as a counter-charge in a lithium salt. As the salt component in PEs, it achieves low anionic diffusivity but sufficient Li-ion conductivity. The ethylene oxide unit in EFA endows nanosized self-agglomeration of anions and trapping interactions between the anions and its structurally homologous matrix, poly(ethylene oxide), thus suppressing the mobility of negative charges. In contrast to previous strategies of using anion traps or tethering anions to a polymer/inorganic backbone, this work offers a facile and elegant methodology on accessing selective and efficient Li-ion transport in PEs and related electrolyte materials (for example, composites and hybrid electrolytes).
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Designing selective inhibitors of proteases has proven problematic, in part because pharmacophores that confer potency exploit the conserved catalytic apparatus. We developed a fundamentally different approach by designing irreversible inhibitors that target noncatalytic cysteines that are structurally unique to a target in a protein family. We have successfully applied this approach to the important therapeutic target HCV protease, which has broad implications for the design of other selective protease inhibitors.
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Inibidores de Cisteína Proteinase/uso terapêutico , Cisteína/antagonistas & inibidores , Desenho de Fármacos , Oligopeptídeos/uso terapêutico , Biocatálise , Bioquímica/métodos , Cristalografia por Raios X , Cisteína/metabolismo , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/crescimento & desenvolvimento , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Virologia/métodosRESUMO
Sulfonimide salts are of great interest for battery use thanks to their special properties including sufficient superior chemical/thermal stabilities, structural flexibility, etc. In particular, the hydrogen-containing sulfonimide (difluoromethanesulfonyl)(trifluoromethanesulfonyl)imide anion {[N(SO2CF2H) (SO2CF3)]-, DFTFSI-}, stands out owing to its suppressed anion mobility and superior electrochemical properties. We herein report the structural analyses of potassium (difluoromethanesulfonyl)(trifluoromethanesulfonyl)imide {K [N(SO2CF2H) (SO2CF3)], KDFTFSI} by virtue of single crystal X-ray diffraction and computational approaches. Our results reveal that KDFTFSI crystallizes in a orthorhombic cell (space group: Pbcn) comprising of cationic and anionic layers, which is similar to the conventional sulfonimide salt, potassium bis(trifluoromethanesulfonyl)imide {K [N(SO2CF3)2], KTFSI}. Gas-phase density functional theory calculations show that the conversion from trans to cis DFTFSI- anions is hindered due to the presence of stabilizing intramolecular H-bonding interactions in the trans conformer; yet interaction with K+ substantially minimizes the energy difference between the two conformers due to the formation of strong tridentate K+ coordination with oxygen atoms in the cis KDFTFSI. This work is anticipated to provide further understanding on the structure-property relations of hydrogenated sulfonimide anions, and thus inspire the structural design of new anions for battery research.
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Polymer electrolytes (PEs) with excellent flexibility and superior compatibility toward lithium (Li) metal anodes have been deemed as one of the most promising alternatives to liquid electrolytes. However, conventional lithium bis(trifluoromethanesulfonyl)imide (LiTFSI)-based dual-ion PEs suffer from a low Li ion transference number and notorious Li dendrite growth. Here, a single-ion conducting polyborate salt without any fluorinated groups, polymeric lithium dihydroxyterephthalic acid borate (PLDPB), is presented for addressing the issues of Li metal batteries. Owing to a nearly immovable bulky anion and the presence of a rigid benzene structure, the PLDPB@poly(ethylene oxide) (PEO) PE exhibits an ultrahigh Li ion transference number (0.94) and excellent mechanical strength, which could significantly restrict the growth of Li dendrites. Postmortem analysis reveals that a fluorine-free solid electrolyte interphase (SEI) enriched with B-O and benzene-containing species is formed on the surface of the Li metal anode, thereby facilitating elimination of excessive parasitic reactions and simultaneously suppressing the formation of Li dendrites. Consequently, the LiFePO4/Li cells with PLDPB@PEO PEs show an improved long-term cycling performance and high capacity retention (90.0%) and Coulombic efficiency (99.9%) after 500 cycles. This work may inspire new ideas to boost the development of single-ion conducting salts for dendrite-free Li metal batteries.
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In lithium-metal batteries (LMBs), the compatibility of Li anode and conventional lithium hexafluorophosphate-(LiPF6 ) carbonate electrolyte is poor owing to the severe parasitic reactions. Herein, to resolve this issue, a delicately designed additive of potassium perfluoropinacolatoborate (KFPB) is unprecedentedly synthesized. On the one hand, KFPB additive can regulate the solvation structure of the carbonate electrolyte, promoting the formation of Li+ FPB- and K+ PF6 - ion pairs with lower lowest unoccupied molecular orbital (LUMO) energy levels. On the other hand, FPB- anion possesses strong adsorption ability on Li anode. Thus, anions can preferentially adsorb and decompose on the Li-anode surface to form a conductive and robust solid-electrolyte interphase (SEI) layer. Only with a trace amount of KFPB additive (0.03 m) in the carbonate electrolyte, Li dendrites' growth can be totally suppressed, and Li||Cu and Li||Li half cells exhibit excellent Li-plating/stripping stability upon cycling. Encouragingly, KFPB-assisted carbonate electrolyte enables high areal capacity LiCoO2 ||Li, LiNi0.8 Co0.1 Mn0.1 O2 (NCM811)||Li, and LiNi0.8 Co0.05 Al0.15 O2 (NCA)||Li LMBs with superior cycling stability, showing its excellent universality. This work reveals the importance of designing novel additives to regulate the solvation structure of carbonate electrolytes in improving its interface compatibility with the Li anode.
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The advent of Li-metal batteries has seen progress toward studies focused on the chemical modification of solid polymer electrolytes, involving tuning either polymer or Li salt properties to enhance the overall cell performance. This study encompasses chemically modifying simultaneously both polymer matrix and lithium salt by assessing ion coordination environments, ion transport mechanisms, and molecular speciation. First, commercially used lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt is taken as a reference, where F atoms become partially substituted by one or two H atoms in the -CF3 moieties of LiTFSI. These substitutions lead to the formation of lithium(difluoromethanesulfonyl)(trifluoromethanesulfonyl)imide (LiDFTFSI) and lithium bis(difluoromethanesulfonyl)imide (LiDFSI) salts. Both lithium salts promote anion immobilization and increase the lithium transference number. Second, we show that exchanging archetypal poly(ethylene oxide) (PEO) with poly(ε-caprolactone) (PCL) significantly changes charge carrier speciation. Studying the ionic structures of these polymer/Li salt combinations (LiTFSI, LiDFTFSI or LiDFSI with PEO or PCL) by combining molecular dynamics simulations and a range of experimental techniques, we provide atomistic insights to understand the solvation structure and synergistic effects that impact macroscopic properties, such as Li+ conductivity and transference number.
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Correction for 'Rational design of Fe3O4@C nanoparticles for simultaneous bimodal imaging and chemo-photothermal therapy in vitro and in vivo' by Qinghe Han et al., J. Mater. Chem. B, 2018, 6, 5443-5450, DOI: 10.1039/C8TB01184B.
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Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer's disease. A structure-activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.
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Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Animais , Camundongos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Introducing a small dose of an electrolyte additive into solid polymer electrolytes (SPEs) is an appealing strategy for improving the quality of the solid-electrolyte-interphase (SEI) layer formed on the lithium metal (Li°) anode, thereby extending the cycling life of solid-state lithium metal batteries (SSLMBs). In this work, we report a new type of SPEs comprising a low-cost, fluorine-free salt, lithium tricyanomethanide, as the main conducting salt and a fluorinated salt, lithium bis(fluorosulfonyl)imide (LiFSI), as the electrolyte additive for enhancing the performance of SPE-based SSLMBs. Our results demonstrate that a homogeneous and stable SEI layer is readily formed on the surface of the Li° electrode through the preferential reductive decomposition of LiFSI, and consequently, the cycle stabilities of Li°||Li° and Li°||LiFePO4 cells are significantly improved after the incorporation of LiFSI as an additive. The intriguing chemistry of the salt anion revealed in this work may expedite the large-scale implementation of SSLMBs in the near future.
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A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5-a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN-211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor.
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Imidazóis/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Piridinas/química , Receptor EphB3/antagonistas & inibidores , Animais , Linhagem Celular , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptor EphB3/metabolismo , Relação Estrutura-AtividadeRESUMO
As a critical signaling node, ERK1/2 are attractive drug targets, particularly in tumors driven by activation of the MAPK pathway. Utility of targeting the MAPK pathway has been demonstrated by clinical responses to inhibitors of MEK1/2 or RAF kinases in some mutant BRAF-activated malignancies. Unlike tumors with mutations in BRAF, those with mutations in KRAS (>30% of all cancers and >90% of certain cancer types) are generally not responsive to inhibitors of MEK1/2 or RAF. Here, a covalent ERK1/2 inhibitor, CC-90003, was characterized and shown to be active in preclinical models of KRAS-mutant tumors. A unique occupancy assay was used to understand the mechanism of resistance in a KRAS-mutant patient-derived xenograft (PDX) model of colorectal cancer. Finally, combination of CC-90003 with docetaxel achieved full tumor regression and prevented tumor regrowth after cessation of treatment in a PDX model of lung cancer. This effect corresponded to changes in a stemness gene network, revealing a potential effect on tumor stem cell reprograming. IMPLICATIONS: Here, a covalent ERK1/2 inhibitor (CC-90003) is demonstrated to have preclinical efficacy in models of KRAS-mutant tumors, which present a therapeutic challenge for currently available therapies.