Pyrazolopyridine Inhibitors of B-Raf<sup>V600E</sup>. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Wenglowsky, Steve; Ren, Li; Ahrendt, Kateri A.; Laird, Ellen R.; Aliagas, Ignacio; Alicke, Bruno; Buckmelter, Alex J.; Choo, Edna F.; Dinkel, Victoria; Feng, Bo; Gloor, Susan L.; Gould, Stephen E.; Größ, Stefan; Gunzner-Toste, Janet; Hansen, Joshua D.; Hatzivassiliou, Georgia; Liu, Bonnie; Malesky, Kim; Mathieu, Simon; Newhouse, Brad; Raddatz, Nicholas J.; Ran, Yingqing; Rana, Sumeet; Randolph, Nikole; Risom, Tyler; Rudolph, Joachim; Savage, Scott W.; Selby, LeAnn T.; Shrag, Michael; Song, Kyung; Sturgis, Hillary L.; Voegtli, W.C.; Wen, Zhaoyang; Willis, Brandon; Woessner, Richard; Wu, Wen-I; Young, Wendy B.; Grina, Jonas

doi:10.1021/ml200025q

Cited by 63 publications

(47 citation statements)

References 30 publications

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“…Now, we know that their potential to stabilize the active kinase conformation allows these inhibitors to activate signaling at subsaturating concentrations where inhibitor-bound RAF molecules can dimerize with and allosterically activate apo RAF molecules, resulting in activation of downstream signaling (Hatzivassiliou et al, 2010; McKay et al, 2011; Poulikakos et al, 2010) (Figure 6A). In contrast, inhibitors like vemurafenib, which stabilizes the Src/CDK-like inactive conformation of RAF (Thevakumaran et al, 2015; Wenglowsky et al, 2011), fail to promote kinase dimerization (Hatzivassiliou et al, 2010) (Figure 6B). Surprisingly, despite this, vemurafenib does induce paradoxical activation of MAPK signaling in cells expressing wild type B-RAF.…”

Section: Exploiting the Dynamic Nature Of The Kinase Domain To Regulamentioning

confidence: 99%

Structural Basis for the Non-catalytic Functions of Protein Kinases

2016

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Summary Protein kinases are known primarily for their ability to phosphorylate protein substrates, which constitutes an essential biological process. Recently, compelling evidence has accumulated that the functions of many protein kinases extend beyond phosphorylation and include an impressive spectrum of non-catalytic roles, such as scaffolding, allosteric regulation, or even protein-DNA interactions. How the conserved kinase fold shared by all metazoan protein kinases can accomplish these diverse tasks in a specific and regulated manner is poorly understood. In this review, we analyze the molecular mechanisms supporting phosphorylation-independent signaling by kinases and attempt to identify common and unique structural characteristics that enable kinases to perform non-catalytic functions. We also discuss how post-translational modifications, protein-protein interactions, and small molecules modulate these non-canonical kinase functions. Finally, we highlight current efforts in the targeted design of small molecule modulators of non-catalytic kinase functions – a new pharmacological challenge for which structural considerations are more important than ever.

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Section: Exploiting the Dynamic Nature Of The Kinase Domain To Regulamentioning

confidence: 99%

Structural Basis for the Non-catalytic Functions of Protein Kinases

2016

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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%

“…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%

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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“…Very recently, a new type of kinase inhibitor, the c-helix-out inhibitor, has been reported, which binds at the ATP-binding site in the DFG-in conformation and shifts the c-helix loop of a kinase to form a new lipophilic pocket in the so-called "c-helix-out conformation." [5][6][7][8][9][10] Once obtained, this type of inhibitor would have outstanding selectivity, because few kinases are known to possess this rare binding mode, and in fact the U.S. Food and Drug Administration (FDA)-approved c-helix-out inhibitors developed so far have highly selective kinase profiles.5,10) Therefore, we consider that preparing these different types simultaneously would be an effective strategy for developing a kinase inhibitor.Transforming growth factor-β-activated kinase 1 (TAK1) is a serine/threonine kinase that plays a pivotal role in inflammatory and immune signaling. TAK1 was discovered by Matsumoto et al as a mitogen-activated kinase kinase kinase (MAP3K) activated by transforming growth factor-β (TGF-β), 11) and since then has been elucidated as a mediator of multiple cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), lipopolysaccharide (LPS), etc.…”

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confidence: 99%

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confidence: 99%

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD)

Muraoka

Ide

Irie

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have developed a method for converting a transforming growth factor-β-activated kinase 1 (TAK1) type I inhibitor into a type II or c-helix-out inhibitor by structure-based drug design (SBDD) to achieve an effective strategy for developing these different types of kinase inhibitor in parallel. TAK1 plays a key role in inflammatory and immune signaling, and is therefore considered to be an attractive molecular target for the treatment of human diseases (inflammatory disease, cancer, etc.). We have already reported novel type I TAK1 inhibitor, so we utilized its X-ray information to design a new chemical class type II and c-helixout inhibitors. To develop the type II inhibitor, we superimposed the X-ray structure of our reported type I inhibitor onto a type II compound that inhibits multiple kinases, and used SBDD to design a new type II inhibitor. For the TAK1 c-helix-out inhibitor, we utilized the X-ray structure of a b-Raf c-helix-out inhibitor to design compounds, because TAK1 is located close to b-Raf in the Sugen kinase tree, so we considered that TAK1 would, similarly to b-Raf, form a c-helix-out conformation. The X-ray crystal structure of the inhibitors in complex with TAK1 confirmed the binding modes of the compounds we designed. This report is notable for being the first discovery of a c-helix-out inhibitor against TAK1.Key words transforming growth factor-β-activated kinase 1 (TAK1); inhibitor; type I; type II; c-helix-out; structure-based drug design Of over 500 kinases in human that maintain the functions of cells, 1) it is not completely clear which kinase inhibition causes an adverse event; therefore, it is important for kinase inhibitors to have a highly selective profile. However, in many cases, kinase inhibitors possess undesired off-target kinase activity, so multiple development candidates with different kinase selectivity profiles need to be prepared, and then a compound with a wide therapeutic window that has no severe adverse effects can be selected as a development candidate. In general, kinase inhibitors are classified into three different types 2,3) : a type I inhibitor binds to the active conformation (DFG-in conformation) of a kinase at the ATP-binding site and competes with ATP; a type II inhibitor binds to both the ATP binding site and its adjacent binding pocket in an inactive conformation (DFG-out conformation) of a kinase; a type III inhibitor is an allosteric inhibitor that has a binding site distinct from the ATP-binding site. Discovery of a type I inhibitor with high kinase selectivity is additionally challenging because amino acid residues in the ATP-binding site are highly conserved in many kinases. On the other hand, it is considered easier to identify a selective type II inhibitor because a type II inhibitor is able to utilize the lipophilic binding pocket derived from the DFG-out conformation, which is less conserved in terms of amino acid residues (though it has recently been reported that not all type II inhibitors possessed high kinase selectivity, 4) so this topic is...

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Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Cited by 63 publications

References 30 publications

Structural Basis for the Non-catalytic Functions of Protein Kinases

Structural Basis for the Non-catalytic Functions of Protein Kinases

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

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD)

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Pyrazolopyridine Inhibitors of B-RafV600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors

Cited by 63 publications

References 30 publications

Structural Basis for the Non-catalytic Functions of Protein Kinases

Structural Basis for the Non-catalytic Functions of Protein Kinases

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

Development of a Method for Converting a TAK1 Type I Inhibitor into a Type II or c-Helix-Out Inhibitor by Structure-Based Drug Design (SBDD)

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Pyrazolopyridine Inhibitors of B-Raf^V600E. Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors