Synthesis and Src Kinase Inhibitory Activity of a Series of 4-Phenylamino-3-quinolinecarbonitriles

Abstract

Screening of a directed compound library in a yeast-based assay identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (2a) as a Src inhibitor. An enzymatic assay established that 2a was an ATP-competitive inhibitor of the kinase activity of Src. We present here SAR data for 2a which shows that the aniline group at C-4, the carbonitrile group at C-3, and the alkoxy groups at C-6 and C-7 of the quinoline are crucial for optimal activity. Increasing the size of the C-2 substituent of the aniline at C-4 of 2a from chloro to bromo to iodo resulted in a corresponding increase in Src inhibition. Furthermore, replacement of the 7-methoxy group of 2a with various 3-heteroalkylaminopropoxy groups provided increased inhibition of both Src enzymatic and cellular activity. Compound 25, which contains a 3-morpholinopropoxy group, had an IC(50) of 3.8 nM in the Src enzymatic assay and an IC(50) of 940 nM for the inhibition of Src-dependent cell proliferation.

Src Inhibition Ameliorates Polycystic Kidney Disease

“…SKI-606 inhibits Src activity in an enzyme assay with an IC50 of 1.2 nM, inhibits anchorage-independent growth of Src-transformed fibroblasts with an IC50 of 100 nM, and inhibits Src-dependent protein tyrosine phosphorylation at comparable or lower concentrations. 47 SKI-606 has an excellent pharmacologic profile after oral administration with a serum half-life of 8.6 h and tissue inhibition of Src (pY-418) Ͼ60% at 24 h. 48 SKI-606 inhibits other Src family kinases but does not directly inhibit growth factor receptor tyrosine kinases such as EGF receptors 1 and 2, PDGF receptor, IGF-I receptor, fibroblast growth factor receptor, and serine-threonine kinases such as AKT and Cdk4. 48 Src Inhibition: In Vivo Studies…”

“…This dosage was based on published pharmacologic and pharmacokinetic data of SKI-606 treatment in mice 47 and preliminary dosage-response studies (data not shown). Animals were treated from PN7 to PN20 (14 doses).…”

“…This dosage was based on published pharmacologic and pharmacokinetic data of SKI-606 treatment in rodents. 47 Animals were treated daily from PN7 to PN89 (82 doses). Kidney and liver were routinely harvested at PN90, and heart, spleen, pancreas, stomach, and thymus were periodically harvested at PN70 to evaluate possible toxicity of vehicle or SKI-606.…”

Screening of Drugs That Suppress Ste11 MAPKKK Activation in Yeast Identified a c-Abl Tyrosine Kinase Inhibitor

“…6). 11N-078 is known as a v-Src kinase inhibitor, 48) suggesting that this compound is a multi kinase-targeting inhibitor. Sorafenib (BY43-90069) and Sunitinib (SU11248) are known multi kinase-targeting inhibitors that act on VEGFR, PDGFR, FLT3, and c-Kit, and have been approved by the FDA.…”

Phosphoproteomics for the Mapping of Altered Cell Signaling Networks in Breast Cancer

“…Recently, Zhang et al modified this approach in order to develop more potent inhibitors of the kinase AXL, which has an important role in mediating breast cancer cell motility and invasivity [45]. In this study, the authors used a chemical library of kinase inhibitors in order to identify small molecular inhibitors with selective activity on the AXL tyrosine kinase, the chemical compound NA80x1which has previously been reported to have inhibitory activity against Src kinase [46], inhibited AXL kinase activity in a dose-dependent manner, with an IC50 of 12.67 ± 0.45 μmol/L. Then, NA80x1 and a structurally similar, but much more potent inhibitor of Src and Abl kinases termed SKI-606, were chemically modified and attached to an affinity purification resin.…”