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Development of paramagnetic probes for molecular recognition studies in protein kinases.

ABSTRACT: We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the resulting compound has nanomolar affinity for JNK despite the relatively weak affinities of the individual fragments that constitute it. The approach demonstrates that targeting the docking site of protein kinases represents a valuable yet unexplored avenue to obtain potent kinase inhibitors with increased selectivity.

SUBMITTER: Vazquez J

PROVIDER: S-EPMC2825083 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Development of paramagnetic probes for molecular recognition studies in protein kinases.

Vazquez Jesus J De Surya K SK Chen Li-Hsing LH Riel-Mehan Megan M Emdadi Aras A Cellitti Jason J Stebbins John L JL Rega Michele F MF Pellecchia Maurizio M

Journal of medicinal chemistry 20080601 12

We report on the synthesis and evaluation of an indazole-spin-labeled compound that was designed as an effective chemical probe for second site screening against the protein kinase JNK using NMR-based techniques. We demonstrate the utility of the derived compound in detecting and characterizing binding events at the protein kinase docking site. In addition, we report on the NMR-based design and synthesis of a bidentate compound spanning both the ATP site and the docking site. We show that the re ...[more]

PMID: 18494454

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