Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

Abstract

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving <i>in vitro</i> probe compound <b>AZ13705339</b> (<b>18</b>). Reduction of lipophilicity to lower clearance afforded <b>AZ13711265</b> (<b>14</b>) as an <i>in vivo</i> probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.