Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src

Abstract

Deregulated activity of the nonreceptor tyrosine kinase c-Src is believed to result in signal transduction, cytoskeletal and adhesion changes, ultimately promoting a tumor-invasive phenotype. We report here the discovery of a new class of anilinoquinazoline inhibitors with high affinity and specificity for the tyrosine kinase domain of the c-Src enzyme. Special attention was directed toward finding inhibitors selective against KDR tyrosine kinase in order to ensure that the in vivo profile of a specific Src inhibitor could be determined. The 4-aminobenzodioxole quinazoline series gave compounds with excellent potency and selectivity. The most interesting compounds were evaluated in vivo and displayed good pharmacokinetics following oral dosing. Compounds such as the aminobenzodioxoles were shown to be potent inhibitors of tumor growth in a c-Src-transformed 3T3 xenograft model in vivo, resulting in more than 90% growth inhibition at doses as low as 6 mg/kg po once daily. Src tyrosine kinase inhibitors such as these may provide a novel therapeutic modality for targeting cancer invasion and metastasis.

Protection from noise-induced hearing loss with Src inhibitors

“…KX2-329, a biaryl-based, non-ATPcompetitive Src inhibitor, and also a tubulin polymerization inhibitor, significantly reduced threshold shifts at 24 h, one week and four weeks after the noise exposure, and also reduced noiseinduced OHC loss. KX2-328, an ATP-competitive Src inhibitor [53], was not effective in reducing NIHL. Overall, the data indicated that the biaryl-based, non-ATP-competitive Src inhibitor KX2-329 was capable of significantly reducing NIHL when present in the cochlea.…”

Investigation of Portable Groundwater Quality and Health Risk Assessment of Selected Trace Metals in Flood Affected Areas of District Rajanpur, Pakistan

“…Similarly, higher contents of Cl in drinking water may create problems in throat and digestive system along with imparting saline taste and corrosion [23]. Alkalinity is also an important parameter of water quality but its concentration beyond certain limit causes many problems like hardness, kidney stone, gas trouble, damage of metallic pipes and severe irritation of skin, eyes and mucous membrane [24]. High level of Na is associated with an increase in blood pressure in children, male and female of all ages [25].…”

Focal adhesion kinase is required for β-catenin-induced mobilization of epidermal stem cells

“…Three main Src family members are present in the epidermis (Src, Fyn and Yes), and initially, we looked at the effect of either homozygous deletion of fyn or yes in Redundancy within the Src family members is known; however, it was not possible to address this genetically due to problems with the viability of the double and triple mutants. Therefore, we used the small molecule kinase inhibitor AZD0530 that inhibits all Src family kinases (30). Prior treatment of animals with AZD0530 resulted in a significant attenuation of the ability of TPA to initiate division of the LRCs ( Figure 2C).…”