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PubMed Journals Articles About "Correction Optimization Fused Bicyclic Allosteric SHP2 Inhibitors" RSS

08:39 EDT 20th May 2019 | BioPortfolio

Correction Optimization Fused Bicyclic Allosteric SHP2 Inhibitors PubMed articles on BioPortfolio. Our PubMed references draw on over 21 million records from the medical literature. Here you can see the latest Correction Optimization Fused Bicyclic Allosteric SHP2 Inhibitors articles that have been published worldwide.

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Showing "Correction Optimization Fused Bicyclic Allosteric SHP2 Inhibitors" PubMed Articles 1–25 of 7,800+

Correction to Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.


Correction to 6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.

A small molecule inhibitor that stabilizes the autoinhibited conformation of the oncogenic tyrosine phosphatase SHP2.

Genetic mutations in the phosphatase PTPN11 (SHP2) are associated with childhood leukemias. These mutations cause hyperactivation of SHP2 due to the disruption of the auto-inhibitory conformation. By targeting the activation-associated protein conformational change, we have identified an SHP2 inhibitor (E)-1-(1-(5-(3-(2,4-dichlorophenyl)acryloyl)-2-ethoxy-4-hydroxybenzyl)-1,2,5,6-tetrahydropyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one (LY6, 1) using computer-aided drug design database screening combined with ...


Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2.

The protein tyrosine phosphatases PTP1B and SHP2 are promising drug targets in treatment design for breast cancer. Searching for specific inhibitors of their activity has recently become the challenge of many studies. Previous work has indicated that the promising PTP inhibitors may be small compounds that are able to bind and interact with amino residues from the binding site.

Association of nuclear localization of SHP2 and YAP1 with unfavorable prognosis in non-small cell lung cancer.

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is ubiquitously expressed in cytoplasmic localization, which in turn confers tumor malignancy and poor prognosis in various human cancers. YAP1 interacts with SHP2 to promote translocation of SHP2 to nucleus, which consequently promotes Wnt target activation. However, the oncogenic role of the nuclear localization of SHP2 in human cancers remains unclear. We hypothesized that nuclear SHP2 localization, in combination with nuclear Y...

Noncanonical Cation-π Cyclizations of Alkylidene β-Ketoesters: Synthesis of Spiro-fused and Bridged Bicyclic Ring Systems.

Three cation-π cyclization cascades initiated at alkylidene β-ketoesters bearing pendent alkenes are described. Depending upon the alkene substitution pattern and the reaction conditions employed, it is possible to achieve selective synthesis of the three different types of products, including 1-halo-3-carbomethoxycyclohexanes, spiro-fused tricyclic systems, and [4.3.1] bridged bicyclic ring systems. All three reactions begin with 6- endo addition of an olefin to the alkylidene β-ketoester electrophile, ...

Bicyclic acetals: biological relevance, scaffold analysis, and applications in diversity-oriented synthesis.

Natural products (NPs) have been shown to be an extraordinary source of bioactive compounds and three-dimensional complex frameworks that can be useful to produce high-value molecular collections that are able to address "undruggable" and difficult therapeutic targets. Bicyclic acetals are particularly relevant for these purposes, given their key role in several biological interactions and the structural and stereochemical diversity that comes from the many possible ring combinations. To investigate this to...

Design and Synthesis of Selective Phosphodiesterase 4D (PDE4D) Allosteric Inhibitors for the Treatment of Fragile X Syndrome and Other Brain Disorders.

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effe...

An Allosteric Metal-Organic Framework Exhibits Multiple Pore Configurations for the Optimization of Hydrocarbon Separation.

The function of allosteric enzymes can be activated or inhibited through binding of specific effector molecules. Here, we found that the skeletal deformation, pore configuration, and ultimately adsorptive behavior of a dynamic metal-organic framework (MOF), [In(atp)2•(MeNH2)]2n (where atp = 2-aminoterephthalate), are controlled by the allocation and orientation of its counter ions triggered by the inclusion/removal of different guest molecules. The power of such allosteric control in MOFs is highlighted i...

First-in-class allosteric inhibitors of bacterial IMPDHs.

Inosine-5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme in many bacterial pathogens and is considered as a potential drug target for the development of new antibacterial agents. Our recent work has revealed the crucial role of one of the two structural domains (i.e. Bateman domain) in the regulation of the quaternary structure and enzymatic activity of bacterial IMPDHs. Thus, we have screened chemical libraries to search for compounds targeting the Bateman domain and identified first in-class ...

Small Molecule Amyloid-β Protein Precursor Processing Modulators Lower Amyloid-β Peptide Levels via cKit Signaling.

Alzheimer's disease (AD) is characterized by the accumulation of neurotoxic amyloid-β (Aβ) peptides consisting of 39-43 amino acids, proteolytically derived fragments of the amyloid-β protein precursor (AβPP), and the accumulation of the hyperphosphorylated microtubule-associated protein tau. Inhibiting Aβ production may reduce neurodegeneration and cognitive dysfunction associated with AD. We have previously used an AβPP-firefly luciferase enzyme complementation assay to conduct a high throughput scr...

Bitopic inhibition of ATP and substrate binding in Ser/Thr kinases through a conserved allosteric mechanism.

Protein kinases achieve substrate selective phosphorylation through their conformation flexibility and dynamic interaction with substrate. Designing substrate selective or kinase selective small molecule inhibitors remains a challenge due to a lack of understanding of the dynamic mechanism by which substrates are selected by the kinase. Using a combination of all-atom MD simulations and FRET sensors, we have delineated an allosteric mechanism that results in interaction between the DFG motif, G-loop, and ac...

SHP2 regulates intramembranous ossification by modifying the TGFβ and BMP2 signaling pathway.

SHP2 is a ubiquitously expressed protein tyrosine phosphatase, which is involved in many signaling pathways to regulate the skeletal development. In endochondral ossification, SHP2 is known to modify the osteogenic fate of osteochondroprogenitors and to impair the osteoblastic transdifferentiation of hypertrophic chondrocytes. However, how SHP2 regulates osteoblast differentiation in intramembranous ossification remains incompletely understood. To address this question, we generated a mouse model to ablate ...

Bicyclic peptides: types, synthesis and applications.

Bicyclic peptides form one of the most promising platforms for drug development owing to their biocompatibility, similarity and chemical diversity to proteins, and they are considered as a possible practical tool in various therapeutic and diagnostic applications. Bicyclic peptides are known to have the capability of being employed as an effective alternative to complex molecules, such as antibodies, or small molecules. This review provides a summary of the recent progress on the types, synthesis and applic...

Design, synthesis and biological evaluation of novel, orally bioavailable pyrimidine-fused heterocycles as influenza PB2 inhibitors.

With the aim to identify novel influenza PB2 inhibitors with high potency and excellent pharmacokinetic parameters, we have designed and synthesized two new series of pyrimidine-fused heterocycle derivatives based on two generations of co-crystal structures. Docking studies with the newly disclosed PDB structure guided the second round of rational design and led to the discovery of 25m, 25o and 25p as representative compounds with improved potency (EC 

Allosteric Modulator Discovery: From Serendipity to Structure-Based Design.

Allosteric modulators bound to structurally diverse allosteric sites can achieve better pharmacological advantages than orthosteric ligands. The discovery of allosteric modulators, however, has been traditionally serendipitous, owing to the complex nature of allosteric modulation. Recent advances in the understanding of allosteric regulatory mechanisms and remarkable availability of structural data of allosteric proteins and modulators, as well as their complexes, have greatly contributed to the development...

Comprehensive assessment of nine docking programs on type II kinase inhibitors: prediction accuracy of sampling power, scoring power and screening power.

Protein kinases have been regarded as important therapeutic targets for many diseases. Currently, a total of 41 kinase inhibitors have been approved by the Food and Drug Administration, along with a large number of kinase inhibitors being evaluated in clinical and preclinical trials. Among all, allosteric inhibitors, such as type II kinase inhibitors, have attracted extensive attention owing to their potential high selectivity. Nowadays, molecular docking has become a powerful tool to search for novel kinas...

SHP2 Drives Adaptive Resistance to ERK Signaling Inhibition in Molecularly Defined Subsets of ERK-Dependent Tumors.

Pharmacologic targeting of components of ERK signaling in ERK-dependent tumors is often limited by adaptive resistance, frequently mediated by feedback-activation of RTK signaling and rebound of ERK activity. Here, we show that combinatorial pharmacologic targeting of ERK signaling and the SHP2 phosphatase prevents adaptive resistance in defined subsets of ERK-dependent tumors. In each tumor that was sensitive to combined treatment, p(Y542)SHP2 induction was observed in response to ERK signaling inhibition...

Bicyclic RGD-peptides with Exquisite Selectivity for the Integrin αvβ3 Receptor using a 'Random Design' Approach.

We describe the identification of bicyclic RGD-peptides with high affinity and selectivity for integrin αvβ3 via high-throughput screening of partly randomized libraries. Peptide libraries (~700 different compounds) comprising the universal integrin-binding sequence Arg-Gly-Asp (RGD) in the first loop and a randomized sequence XXX (X being one of 18 canoni-cal L-amino acids) in the second loop, both enclosed by either an L- or D-Cys residue, were converted to bicyclic peptides via reaction with 1,3,5-tris...

Discovery, X-ray Crystallography and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease.

Flaviviruses, including dengue, West Nile and recently emerged Zika virus, are important human pathogens, but there are no drugs to prevent or treat these viral infections. The highly conserved Flavivirus NS2B-NS3 protease is essential for viral replication and therefore a drug target. Compound screening followed by medicinal chemistry yielded a series of drug-like, broadly active inhibitors of Flavivirus proteases with IC as low as 120 nM. The inhibitor exhibited significant antiviral activities in cells (...

Structure-Activity Relationships of Hexahydrocyclopentacquinoline Derivatives as Allosteric Inhibitors of CDK2 and EGFR.

Following the discovery of a type III allosteric modulator of cyclin-dependent kinase 2 (CDK2) characterized by a hexahydrocyclopenta[c]quinolone scaffold, three different series of its derivatives were synthesized and biologically evaluated. Docking of the synthesized compounds into the allosteric pocket of CDK2 allowed the elucidation of structure-activity relationships (SARs). Moreover, the compounds were tested on the wild-type epidermal growth factor receptor (EGFR) kinase domain (KD) and its clini...

Allosteric regulation of pyruvate kinase from Mycobacterium tuberculosis by metabolites.

Mycobacterium tuberculosis (Mtb) causes both acute tuberculosis and latent, symptom-free infection that affects roughly one-third of the world's population. It is a globally important pathogen that poses multiple dangers. Mtb reprograms its metabolism in response to the host niche, and this adaptation contributes to its pathogenicity. Knowledge of the metabolic regulation mechanisms in Mtb is still limited. Pyruvate kinase, involved in the late stage of glycolysis, helps link various metabolic routes togeth...

Discovery of N-substituted 7-azaindoles as Pan-PIM kinases inhibitors - Lead optimization - Part III.

N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.

Rational Design and Identification of Small-Molecule Allosteric Inhibitors of CD38.

CD38 is a multi-functional signaling enzyme, catalyzing the biosynthesis of two calcium-mobilizing second messengers, cyclic ADP-ribose and nicotinic acid adenosine dinucleotide phosphate. It also regulates intracellular NAD contents, which is associated with multiple pathophysiological processes such as aging and cancer. As thus, the enzymatic inhibitors is of great potential in drug development. Herein, through the virtual screening and enzymatic assays, we discovered compound LX-102, targeting the opposi...

Synthesis, biological evaluation, and computational studies of novel fused six-membered O-containing heterocycles as potential acetylcholinesterase inhibitors.

An efficient, borax-catalyzed protocol for the synthesis of novel 4-aryl-substituted-4H-pyran derivatives fused to α-pyrone ring in a one-pot is described. By this achievement, some novel 4-aryl substituted 4H-pyrans fused to the α-pyrone ring as potential acetylcholinesterase inhibitors (AChEIs) with good to excellent yields are obtained from a one-pot three-component reaction between various aryl aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one and malononitrile. The method is a facile, inexpensive, practic...


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