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Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors

DOI: 10.1021/acsmedchemlett.6b00322 DOI Help

Authors: William Mccoull (AstraZeneca) , Edward J. Hennessy (AstraZeneca) , Kevin Blades (AstraZeneca) , Claudio Chuaqui (AstraZeneca) , James E. Dowling (AstraZeneca) , Andrew D. Ferguson (AstraZeneca) , Frederick W. Goldberg (AstraZeneca) , Nicholas Howe (AstraZeneca) , Christopher R. Jones (AstraZeneca) , Paul D. Kemmitt (AstraZeneca) , Gillian Lamont (AstraZeneca) , Jeffrey G. Varnes (AstraZeneca) , Richard A. Ward (AstraZeneca) , Bin Yang (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 7 , PAGES 1118 - 1123

State: Published (Approved)
Published: December 2016

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.

Journal Keywords: bis-anilino pyrimidine; kinase selectivity; LLE; PAK; probe

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography