Pyrazolopyridine inhibitors of B-RafV600E. Part 2: Structure–activity relationships

Wenglowsky, Steve; Ahrendt, Kateri A.; Buckmelter, Alex J.; Feng, Bo; Gloor, Susan L.; Gradl, Stefan; Grina, Jonas; Hansen, Joshua D.; Laird, Ellen R.; Lunghofer, Paul J.; Mathieu, Simon; Moreno, David; Newhouse, Brad; Ren, Li; Risom, Tyler; Rudolph, Joachim; Seo, Jeongbeob; Sturgis, Hillary L.; Voegtli, W.C.; Wen, Zhaoyang

doi:10.1016/j.bmcl.2011.06.097

Cited by 52 publications

(44 citation statements)

References 18 publications

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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%

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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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Section: Methodology Datasetmentioning

confidence: 99%

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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“…Standing on the predicted binding modes, compounds may be improved by substitution of the 2‐(methylamino) ethanol moiety on compound 1 or (2R)‐2‐methoxypropanamide moiety on compound 8 with groups able to interact by hydrogen bonding with the residues of the DFG motif region (e.g., amides, solphonamides, and ureas) . Moreover, further substitutions at the distal portion of the identified scaffold with groups able to fill the subpocket lined by Leu505, Ile513, Leu514, and Glu501 residues, such as aromatic or aliphatic rings, look particularly promising to improve affinity for B‐Raf . Finally, the lack of Hsp90 inhibitory activity of compounds 1–10 may be due to the fact that the 1 H ‐pyrrole[2,3‐b]pyridine moiety is not sufficiently decorated with polar groups able to participate to the extended hydrogen bonding network involving Asp93, Thr184, and three to four conserved water molecules that are formed by most active Hsp90 inhibitors …”

Section: Inhibitory Activity Of the Discussed Compoundsmentioning

confidence: 99%

Identification of 4‐aryl‐1H‐pyrrole[2,3‐b]pyridine derivatives for the development of new B‐Raf inhibitors

et al. 2018

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During the last years, a significant interest in the identification of new classes of B-Raf inhibitors has emerged. In this study, which was conceived within an effort that culminated in the recent report of the first dual inhibitors of B-Raf and Hsp90, we describe the identification of four compounds based on 4-aryl-1H-pyrrole[2,3-b]pyridine scaffold as interesting starting points for the development of new B-Raf inhibitors. Structure-activity relationships and predicted binding modes are discussed. Moreover, the novelty of the newly identified structures with respect to currently known B-Raf inhibitors was assessed through a ligand-based dissimilarity assessment. Finally, structural modifications with the potential ability to improve the activity toward B-Raf are put forward.

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“…Both 3 and 4 showed high activity against several melanoma and BRAF‐mutated colon cancer cell lines, with nanomolar IC 50 values and favorable pharmacokinetic profiles. Therefore, they were selected to proceed in preclinical assays 37…”

Section: Targeting the Mapk Or Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Targets, Structures, and Recent Approaches in Malignant Melanoma Chemotherapy

Matos

Francisco

2013

ChemMedChem

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Malignant metastatic melanoma is one of the oncologic diseases with the worst clinical prognosis, due primarily to resistance phenomena against chemotherapeutic agents in current use. However, over the last few years, characterization of the molecular mechanisms involved in the development and progression of the disease has contributed to elucidation of the main pathways by which tissue invasion and metastasis can occur. More importantly, the identification of abnormalities in signaling cascades in melanoma cells has facilitated new therapeutic approaches against malignant melanoma through the design of highly potent and selective drugs with low associated toxicity. Ultimately, recognition of the restricted applicability of new chemotherapies in certain genetic contexts has led to significant improvements in the results of clinical trials, anticipating the existing need for investment in personalized therapies, and taking into account the molecular alterations observed in tumors. Although significant advances have been made in terms of extending the median overall survival rate and improving the quality of life for patients, the mechanisms that compromise in vivo drug efficacy remain poorly understood, particularly those concerning therapeutic resistance phenomena. This review summarizes recently validated targets from the perspective of the medicinal chemistry carried out in the design of the most promising structures.

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Pyrazolopyridine inhibitors of B-RafV600E. Part 2: Structure–activity relationships

Cited by 52 publications

References 18 publications

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

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

Identification of 4‐aryl‐1H‐pyrrole[2,3‐b]pyridine derivatives for the development of new B‐Raf inhibitors

Targets, Structures, and Recent Approaches in Malignant Melanoma Chemotherapy

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