Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology and neurology. We have identified N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. We demonstrated its efficacy in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A 11C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.
The SH2 domain of pp60c-src (Src), a nonreceptor
tyrosine kinase, facilitates signal transduction in a
number of cell types through binding to cognate phosphorylated protein
sequences. Phosphotyrosine-containing
peptides have been shown to bind to the Src SH2 domain with micromolar
affinity. Guided by the X-ray crystal
structure of a phosphorylated peptide bound to the Src SH2 domain, we
have designed a de novo series of small
molecule ligands that bind with affinity comparable to the parent
phosphopeptide. An X-ray crystal structure of the
Src SH2 domain bound with a nonpeptide analog from this series verifies
interactions targeted in the molecular
design. However, a unique mode of binding has been revealed for
the P-site phenyl phosphate group of the nonpeptide
that differs from that observed for the phosphotyrosine side chain in
peptide ligands bound to the Src SH2 domain.
This novel binding mode is being used in guiding future design
efforts.
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