Structure based design of novel, single-digit nM benzotriazine Src inhibitors.

Abstract

The tyrosine kinase Src plays a key role in vascular permeability, tumor progression and metastasis. Due to the pivotal role of Src in cell signaling pathways, Src inhibitors may be useful therapeutics for the treatment of cancers and other diseases including myocardial infarction, osteoporosis, stroke, and neurodegeneration. TargeGen has designed a series of novel benzotriazines that are used to target Src. Suzuki-Miyaura cross coupling chem. was used to construct the 7-(2, 6-dimethylphenyl)-benzotriazine intermediates from the corresponding 2,6-disubstituted Ph boronic acid and 7-bromo-benzotriazine cores. The series was optimized to obtain single-digit nM inhibitors of Src via elaboration of the R1 and R2 groups. The details of this campaign and the resulting SAR from these modifications will be presented. [on SciFinder(R)]