Pyrazolopyridine inhibitors of B-RafV600E. Part 4: Rational design and kinase selectivity profile of cell potent type II inhibitors

Wenglowsky, Steve; Moreno, David; Laird, Ellen R.; Gloor, Susan L.; Ren, Li; Risom, Tyler; Rudolph, Joachim; Sturgis, Hillary L.; Voegtli, W.C.

doi:10.1016/j.bmcl.2012.08.007

Cited by 27 publications

(26 citation statements)

References 21 publications

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“…Although type I BRAF inhibitors are effective against the oncogenic BRAF-V600E mutant, these molecules are usually strong dimer-promoting agents causing paradoxical activation in the BRAF-WT cells. Type II BRAF inhibitors [ 53–58 ] that stabilize the inactive DFG-out/αC-helix-in conformation can also stimulate enzyme transactivation by favoring an αC-helix-in position that promotes side-to-side dimerization ( Fig 1 ). The crystal structures of the BRAF-WT and BRAF-V600E complexes with the FDA-approved Sorafenib (pdb id 1UWH, 1UWJ) have demonstrated that type II inhibitors that strongly bind to both monomers and exhibit long residence time may be relatively weak dimer inducers [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Tse

Verkhivker

2016

PLoS ONE

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The recent studies have revealed that most BRAF inhibitors can paradoxically induce kinase activation by promoting dimerization and enzyme transactivation. Despite rapidly growing number of structural and functional studies about the BRAF dimer complexes, the molecular basis of paradoxical activation phenomenon is poorly understood and remains largely hypothetical. In this work, we have explored the relationships between inhibitor binding, protein dynamics and allosteric signaling in the BRAF dimers using a network-centric approach. Using this theoretical framework, we have combined molecular dynamics simulations with coevolutionary analysis and modeling of the residue interaction networks to determine molecular determinants of paradoxical activation. We have investigated functional effects produced by paradox inducer inhibitors PLX4720, Dabrafenib, Vemurafenib and a paradox breaker inhibitor PLX7904. Functional dynamics and binding free energy analyses of the BRAF dimer complexes have suggested that negative cooperativity effect and dimer-promoting potential of the inhibitors could be important drivers of paradoxical activation. We have introduced a protein structure network model in which coevolutionary residue dependencies and dynamic maps of residue correlations are integrated in the construction and analysis of the residue interaction networks. The results have shown that coevolutionary residues in the BRAF structures could assemble into independent structural modules and form a global interaction network that may promote dimerization. We have also found that BRAF inhibitors could modulate centrality and communication propensities of global mediating centers in the residue interaction networks. By simulating allosteric communication pathways in the BRAF structures, we have determined that paradox inducer and breaker inhibitors may activate specific signaling routes that correlate with the extent of paradoxical activation. While paradox inducer inhibitors may facilitate a rapid and efficient communication via an optimal single pathway, the paradox breaker may induce a broader ensemble of suboptimal and less efficient communication routes. The central finding of our study is that paradox breaker PLX7904 could mimic structural, dynamic and network features of the inactive BRAF-WT monomer that may be required for evading paradoxical activation. The results of this study rationalize the existing structure-functional experiments by offering a network-centric rationale of the paradoxical activation phenomenon. We argue that BRAF inhibitors that amplify dynamic features of the inactive BRAF-WT monomer and intervene with the allosteric interaction networks may serve as effective paradox breakers in cellular environment.

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Section: Introductionmentioning

confidence: 99%

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Tse

Verkhivker

2016

PLoS ONE

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“…To perform a 3D-QSAR analysis, a collection of 98 compounds and their corresponding biological activities (IC 50 ) was acquired from the literature [17,[19][20][21]. The IC 50 (nM) values of these compounds were converted into logarithmic scale [pIC 50 (M)] to provide numerically larger data values.…”

Section: Methodology Datasetmentioning

confidence: 99%

“…To perform a docking analysis, AutoDock 4.2 [61] was used to understand the interactions between the most potent B-raf 600E inhibitor in the data set and this kinase. The related protein complex was selected from protein databank (http://www.rcsb.org) with the PDB ID of 4G9C [17] which is based on the 3.5 Å resolution X-ray crystal structure of human B-Raf kinase. Before performing the docking procedures, the protein structure was prepared by removing all water molecules, and then polar hydrogen atoms and Kollman charges were added to the protein structure [62].…”

Section: Molecular Dockingmentioning

confidence: 99%

“…Several studies have been conducted to introduce new B-Raf inhibitors [8,11,[13][14][15][16][17][18]. Recently, Wenglowsky and co-workers [17,[19][20][21] designed a large number of new and potent B-Raf inhibitors, which were selective for the BRaf V600E gene.…”

Section: Introductionmentioning

confidence: 98%

“…Recently, Wenglowsky and co-workers [17,[19][20][21] designed a large number of new and potent B-Raf inhibitors, which were selective for the BRaf V600E gene. These series of inhibitors were derived from the pyrazolopyridine moiety, and then further assessed using bicyclic cores (imidazopyridine, pyrrolopyridine) [17,[19][20][21]. Researchers have also reported new and potent inhibitors with improved solubility after linking the pyrazolopyridine moiety to hydrogen bond donor groups [17,20].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of B-Raf $$^{\mathrm{V600E}}$$ V 600 E inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies

Aalizadeh

Pourbasheer

2015

Mol Divers

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In the present work, a molecular modeling study was carried out using 2D and 3D quantitative structure-activity relationships for the various series of compounds known as B-Raf[Formula: see text] inhibitors. For 2D-QSAR analysis, a linear model was developed by MLR based on GA-OLS with appropriate results [Formula: see text], which was validated by several external validation techniques. To perform a 3D-QSAR analysis, CoMFA and CoMSIA methods were used. The selected CoMFA model could provide reliable statistical values [Formula: see text] based on the training set in the biases of the selected alignment. Using the same selected alignment, a statistically reliable CoMSIA model, out of thirty-one different combinations, was also obtained [Formula: see text]. The predictive accuracy of the derived models was rigorously evaluated with the external test set of nineteen compounds based on several validation techniques. Molecular docking simulations and pharmacophore analyses were also performed to derive the true conformations of the most potent inhibitors with B-Raf[Formula: see text] kinase.

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Identification and Biological Evaluation of Novel Type II B‐Raf^V600E Inhibitors

Wang

Qiu

et al. 2018

ChemMedChem

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The mitogen‐activated protein kinase (MAPK) pathway plays a vital role in signal transduction networks. Severe diseases may be triggered if it is disturbed by mutated components, especially the kinase B‐RafV600E. New inhibitors of the kinase are needed as cases of relapse and resistance with the known drugs have been widely reported in the clinic. In the present work, a new class of B‐RafV600E inhibitors was identified by fragment linking. In vitro and in vivo assays were used to demonstrate the pharmacological properties of the compounds. 3‐{3‐[4‐Chloro‐3‐(trifluoromethyl)phenyl]ureido}‐N‐[1‐(4‐methoxyphenyl)‐1H‐pyrazol‐4‐yl]benzamide was the most potent agent with IC50 values of 0.035±0.004 μm (B‐RafV600E kinase) and 0.39±0.04 μm (A375 cells). Furthermore, no obvious toxicity was observed. Collectively, the results favored justified the design rationale and hinted that this new chemotype might be worth studying further to develop novel B‐Raf inhibitor candidates.

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Pyrazolopyridine inhibitors of B-RafV600E. Part 4: Rational design and kinase selectivity profile of cell potent type II inhibitors

Cited by 27 publications

References 21 publications

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Analysis of B-Raf $$^{\mathrm{V600E}}$$ V 600 E inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies

Identification and Biological Evaluation of Novel Type II B‐Raf^V600E Inhibitors

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Pyrazolopyridine inhibitors of B-RafV600E. Part 4: Rational design and kinase selectivity profile of cell potent type II inhibitors

Cited by 27 publications

References 21 publications

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Exploring Molecular Mechanisms of Paradoxical Activation in the BRAF Kinase Dimers: Atomistic Simulations of Conformational Dynamics and Modeling of Allosteric Communication Networks and Signaling Pathways

Analysis of B-Raf $$^{\mathrm{V600E}}$$ V 600 E inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies

Identification and Biological Evaluation of Novel Type II B‐RafV600E Inhibitors

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Identification and Biological Evaluation of Novel Type II B‐Raf^V600E Inhibitors