<i>N</i>-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors

Li, Yingjun; Cheng, Huimin; Zhang, Zhang; Zhuang, Xiaoxi; Luo, Jinfeng; Long, Huoyou; Zhou, Yang; Xu, Yong; Taghipouran, Rana; Li, Dan; Patterson, Adam V.; Smaill, Jeff B.; Tu, Zhengchao; Wu, Donghai; Ren, Xiaomei; Ding, Ke

doi:10.1021/acsmedchemlett.5b00039

Cited by 34 publications

(35 citation statements)

References 22 publications

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“…For dabrafenib, PK, protein binding, and cell potency data in the same cell line were available to estimate the relative contribution of parent and active metabolites to the activity and thus to estimate the overall effective C ss /IC 50 for the drug ( Table 2 ). COLO205 cell line potency was used to estimate C ss /IC 50 for all BRAF and MEK1/2 inhibitors, with the exception of encorafenib, which used A375 cell line data 17–19 . COLO205 is a colorectal adenocarcinoma cell line, whereas A375 is a melanoma cell line.…”

Section: Methodsmentioning

confidence: 99%

“…COLO205 cell line potency was used to estimate C ss /IC 50 for all BRAF and MEK1/2 inhibitors, with the exception of encorafenib, which used A375 cell line data. [17][18][19] COLO205 is a colorectal adenocarcinoma cell line, whereas A375 is a melanoma cell line. Both have a V600E mutations that constitutively activate the MAP kinase pathway.…”

Section: Braf Mek Inhibitorsmentioning

confidence: 99%

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Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

Goldstein

Peters

Weber

et al. 2020

Clinical Translational Sci

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Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP‐ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady‐state concentration (C ss ) at the approved dose was compared to the in vitro cell potency (half‐maximal inhibitory concentration (IC 50 )). Average steady‐state area under the plasma concentration‐time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer‐reviewed journal articles. The C ss was remarkably similar to the IC 50 . The median C ss /IC 50 value was 1.2, and 76% of the values were within 3‐fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a C ss /IC 50 value > 25. Seven other therapies targeting the same 3 kinases had much lower C ss /IC 50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first‐in‐human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and C ss exceeds a potency threshold. This potency‐guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.

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Section: Methodsmentioning

confidence: 99%

Section: Braf Mek Inhibitorsmentioning

confidence: 99%

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

Goldstein

Peters

Weber

et al. 2020

Clinical Translational Sci

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“…Most authors use hydrazine hydrate as the initial reactant, using ethanol as solvent at reflux temperature; the reaction time needed ranges from 2 h to more than 15 h [ 93 , 94 , 95 , 96 ]. Arafa and Hussein performed the reaction at 50 °C using a sonicator, allowing them to obtain the product in 15 min [ 97 ].…”

Section: Synthetic Approaches To 1 H -Pyrazolo[34-...mentioning

confidence: 99%

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

et al. 2022

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Pyrazolo[3,4-b]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1H- and 2H-isomers. More than 300,000 1H-pyrazolo[3,4-b]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds.

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“…[16][17] In addition, hetreobiaryle pyrazolopyridine (1H-pyrazolo [3,4-b]pyridine) considerable important in the group of fused heterocycles which has shown the most powerful therapeutic activity. Pyrazolo [3,4-b]pyridine show large numbers of significant biological properties such as antimicrobial 18 , antiviral 19 , antitumer 18 , analgesic 20 , anti inflammatory 21 , cyclooxygenase-(COX) inhibitors 21 , selective c-Met inhibitors 22 , selective Raf inhibitors 23 , antioxidant activities 24 , etc.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and characterization of 4-((5-bromo-1H-pyrazolo [3,4-b]pyridin-3-yl)amino)-N-(substituted)benzenesulfonamide as Antibacterial, and Antioxidant Candidates

Variya¹,

Panchal²,

Patel³

2019

10.5267/j.ccl

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A series of novel 5-Bromo-3-iodo-1H-pyrazolo [3,4-b]pyridine linked various sulfonamide derivatives 8a-8j poly functionalized were designed and synthesized in moderate to good yield. A starting with iodination of 5-with the reaction of various sulfonamide derivatives 7a-7j via copper catalyzed coupling reaction produced targeted compounds8a-8j. The isolated compounds were accepted by spectral and elemental analysis. The compounds 8a,8c,8d, and 8i were excellent active against Gram-positive and gram-negative bacterial strain compare to streptomycin standard drug. All synthesized compounds showed moderate to good antioxidant properties with used DPPH and Superoxide radical scavenging assay, Compounds 8c, 8g, and 8i exerted significant antioxidant scavenging activity for the DPPH radical.

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N-(3-Ethynyl-2,4-difluorophenyl)sulfonamide Derivatives as Selective Raf Inhibitors

Cited by 34 publications

References 22 publications

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency‐Guided First‐in‐Human Studies

1H-Pyrazolo[3,4-b]pyridines: Synthesis and Biomedical Applications

Synthesis and characterization of 4-((5-bromo-1H-pyrazolo [3,4-b]pyridin-3-yl)amino)-N-(substituted)benzenesulfonamide as Antibacterial, and Antioxidant Candidates

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