N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: Indazoles as phenol isosteres with improved pharmacokinetics

Bamborough, Paul; Angell, Richard; Bhamra, Inder; Brown, David F.M.; Bull, James A.; Christopher, John; Cooper, Anthony W. J.; Fazal, Lynsey; Giordano, Ilaria; Hind, Lucy; Patel, Vipulkumar K.; Ranshaw, Lisa E.; Sims, Martin; Skone, Philip A.; Smith, Kathryn J.; Vickerstaff, Emma; Washington, Melanie

doi:10.1016/j.bmcl.2007.04.029

Cited by 47 publications

(39 citation statements)

References 14 publications

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“…The chemotypes from the GSK PKIS that give rise to FLuc inhibition target both protein tyrosine kinases [23], [24], [25], [26], [27] and S/T kinases [28], [29], [30], [31], [32], [33], [34] as listed in Table 3 . Structural clustering of the library members using Tanimoto coefficients [35] results in the 47 groups shown in Figure 2A and defined here by their original literature target kinase(s).…”

Section: Resultsmentioning

confidence: 99%

Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

et al. 2013

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A library of 367 protein kinase inhibitors, the GSK Published Kinase Inhibitor Set (PKIS), which has been annotated for protein kinase family activity and is available for public screening efforts, was assayed against the commonly used luciferase reporter enzymes from the firefly, Photinus pyralis (FLuc) and marine sea pansy, Renilla reniformis (RLuc). A total of 22 compounds (∼6% of the library) were found to inhibit FLuc with 10 compounds showing potencies ≤1 µM. Only two compounds were found to inhibit RLuc, and these showed relatively weak potency values (∼10 µM). An inhibitor series of the VEGFR2/TIE2 protein kinase family containing either an aryl oxazole or benzimidazole-urea core illustrate the different structure activity relationship profiles FLuc inhibitors can display for kinase inhibitor chemotypes. Several FLuc inhibitors were broadly active toward the tyrosine kinase and CDK families. These data should aid in interpreting the results derived from screens employing the GSK PKIS in cell-based assays using the FLuc reporter. The study also underscores the general need for strategies such as the use of orthogonal reporters to identify kinase or non-kinase mediated cellular responses.

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Section: Resultsmentioning

confidence: 99%

Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

et al. 2013

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“…We believe that TG003 is easily metabolized via O -demethylation and subsequent sulfate conjugation of the hydroxyl group38 and likely interacts with CLK1 via hydrogen bonds in the ATP-binding pocket39. In the case of TG693, metabolically stable indazole moiety is suspected to form a hydrogen bond with an amino acid residues of CLK140, but structural studies will be necessary to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

Sako

Ninomiya

Okuno

et al. 2017

Sci Rep

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Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein. Oral administration of TG693 to mice inhibited the phosphorylation of serine/arginine-rich proteins, which are the substrates of CLK1, and modulated pre-mRNA splicing in the skeletal muscle. Thus, TG693 is a splicing modulator for the mutated exon 31 of the dystrophin gene in vivo, possibly possessing therapeutic potential for DMD patients.

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“…(4) Introducing nitrogen atom(s) on the indazole motif (azaindole) provides another approach to optimization, as the reduced clog P values may improve potency. (5) Indazole motif could improve pharmacokinetic properties . (6) Alkaline fragments such as piperazine, piperidine, morpholine, and aliphatic amine are widely found in indazole‐containing analogues, which are attributed to improving solubility and activity.…”

Section: Discussionmentioning

confidence: 99%

“…( 5) Indazole motif could improve pharmacokinetic properties. [101] (6) Alkalinef ragments such as piperazine, piperidine, morpholine, and aliphatic amine are widely found in indazole-containing analogues, which are attributed to improving solubility anda ctivity.I n general, fine-tuning the substituents on the indazole backbone may afford novel molecules with enhanced anticancer potency, as well as drug-likep roperties.…”

Section: Discussionmentioning

confidence: 99%

Recent Advances in the Development of Indazole‐based Anticancer Agents

et al. 2018

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Cancer is one of the leading causes of human mortality globally; therefore, intensive efforts have been made to seek new active drugs with improved anticancer efficacy. Indazole-containing derivatives are endowed with a broad range of biological properties, including anti-inflammatory, antimicrobial, anti-HIV, antihypertensive, and anticancer activities. In recent years, the development of anticancer drugs has given rise to a wide range of indazole derivatives, some of which exhibit outstanding activity against various tumor types. The aim of this review is to outline recent developments concerning the anticancer activity of indazole derivatives, as well as to summarize the design strategies and structure-activity relationships of these compounds.

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N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: Indazoles as phenol isosteres with improved pharmacokinetics

Cited by 47 publications

References 14 publications

Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

Profile of the GSK Published Protein Kinase Inhibitor Set Across ATP-Dependent and-Independent Luciferases: Implications for Reporter-Gene Assays

Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

Recent Advances in the Development of Indazole‐based Anticancer Agents

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