ACS Med Chem Lett. 2016; 7(12):
1118-1123.
Optimization of Highly Kinase Selective Bis-anilino
Pyrimidine PAK1 Inhibitors.
McCoull W1,
Hennessy EJ2,
Blades K3,
Chuaqui C2,
Dowling JE2,
Ferguson AD2,
Goldberg FW1,
Howe N3,
Jones CR3,
Kemmitt PD1,
Lamont G1,
Varnes JG2,
Ward RA1,
Yang B2.
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 in vitro probe
compound AZ13705339 (18). Reduction of lipophilicity to lower
clearance afforded AZ13711265 (14) as an in vivo probe
compound with oral exposure in mouse. Such probes will allow further
investigation of PAK1 biology.
Potent and selective Kv3.4 potassium channel blocker (IC50 = 47 nM). Also potent TTX-sensitive sodium channel agonist (EC50 = 3 nM). Exhibits neuroprotective effect. BDS I
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