Structure−Activity Relationships for a Novel Series of Pyrido[2,3-d]pyrimidine Tyrosine Kinase Inhibitors

Abstract

Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- tert-butylurea (4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound 4b inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50 values of 1.11, 0.13, 0.45, and 0.22 microM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2-position of 4b afforded compound 6c with enhanced potency and bioavailability. Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC50 of 0.3 microM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with a 6-(3',5'-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor 4e. Compound 4e inhibited the FGFr tyrosine kinase with an IC50 of 0.060 microM, whereas IC50s for the inhibition of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 microM.

Induced Focal Adhesion Kinase (FAK) Expression in FAK-Null Cells Enhances Cell Spreading and Migration Requiring Both Auto- and Activation Loop Phosphorylation Sites and Inhibits Adhesion-Dependent Tyrosine Phosphorylation of Pyk2

“…The pyrido [2,3-d] pyrimidine tyrosine kinase inhibitor PD161430 (compound 4f in the work of Hamby et al [22]) was assessed for its efficacy in inhibiting the kinase activities of Src and FAK. Previously, PD161430 was shown to inhibit c-Src activity toward poly(GluTyr) with a 50% inhibitory concentration of 0.22 M (22).…”

“…The pyrido [2,3-d] pyrimidine tyrosine kinase inhibitor PD161430 (compound 4f in the work of Hamby et al [22]) was assessed for its efficacy in inhibiting the kinase activities of Src and FAK. Previously, PD161430 was shown to inhibit c-Src activity toward poly(GluTyr) with a 50% inhibitory concentration of 0.22 M (22). To measure Src activity toward p120 ctn , NIH 3T3 cells stably expressing the F527 activating mutant of chicken c-Src were lysed in NP-40 buffer, and Src and p120 ctn were immunoprecipitated together on protein A-Sepharose beads with a mixture of monoclonal antibodies 327 and 15D2, followed by rabbit anti-mouse IgG.…”

A class of selective antibacterials derived from a protein kinase inhibitor pharmacophore

“…Consistent with this hypothesis, we used unbiased whole-bacterial cell screening of the Pfizer compound library to discover a series of antibacterial pyridopyrimidines (1, 2, and 3; Fig. 1A) that emerged from a structurebased drug design program targeting eukaryotic tyrosine protein kinases (5). By using genetic and biochemical tools, the bacterial target of these compounds was identified as biotin carboxylase (BC); one portion of the acetyl-CoA carboxylase (ACCase) multienzyme complex responsible for the first step of fatty acid biosynthesis (6).…”

SUN11602, a Novel Aniline Compound, Mimics the Neuroprotective Mechanisms of Basic Fibroblast Growth Factor

“…The phosphorylation of FGFR-1 is an inevitable step in the neuroprotective mechanisms of SUN11602 because PD166866 has been shown to abolish the receptor-mediated effects. 19 However, SUN11602 does not obstruct the binding of 125 I-labeled bFGF to the extracellular domain of FGFR-1 (unpublished data). These results imply that SUN11602 can either directly or indirectly trigger the phosphorylation of the cytosolic domain of FGFR-1 without acting on the extracellular bFGF-binding site.…”

“…The neuroprotective effects of SUN11602 and bFGF were completely antagonized when PD166866 (0.3 μM) was added to the cultures of cortical neurons 30 min before the application of SUN11602 and bFGF ( Figure 3A). PD166866, which is a specific inhibitor of the FGFR-1 tyrosine kinase (IC 50 of approximately 52 nM), 19 is regarded as being selective for but less effective on the tyrosine kinases of the platelet-derived growth factor receptor (PDGFR), the epidermal growth factor receptor (EGFR), the insulin-like growth factor-1 receptor 24 PDGFR, 25 and vascular endothelial growth factor receptor (VEGFR) 26 were investigated in order to clarify whether PD166866 inhibited neuroprotection as a result of the phosphorylation of the tyrosine kinase domains of these receptors. Because the binding of natural ligands to the corresponding receptors has been established to induce actions that protect vulnerable neurons, the inhibitory effects of PD166866 on these receptors were examined in the cultured cortical neurons by MTT assay ( Figure 3B).…”