title: 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, givingin vitroprobe compoundAZ13705339(18). Reduction of lipophilicity to lower clearance affordedAZ13711265(14) as anin vivoprobe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.
authors.affiliation: AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: William
authors.initials: W
authors.lastname: McCoull
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
authors.forename: Kevin
authors.initials: K
authors.lastname: Blades
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Dowling
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ferguson
authors.affiliation: AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Goldberg
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Howe
authors.affiliation: AstraZeneca , Alderley Park, Macclesfield, Cheshire, SK10 4TG, U.K.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Kemmitt
authors.affiliation: AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Gillian
authors.initials: G
authors.lastname: Lamont
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Varnes
authors.affiliation: AstraZeneca , 310 Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, U.K.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ward
authors.affiliation: AstraZeneca , Gatehouse Park, Waltham, Massachusetts 02451, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
keywords: LLE; PAK; bis-anilino pyrimidine; kinase selectivity; probe