title: Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series.
abstract: To increase kinase selectivity in an aminopyrazole-based PAK1 inhibitor series, analogues were designed to interact with the PAK1 deep-front pocket pre-DFG residue Thr-406, a residue that is hydrophobic in most kinases. This goal was achieved by installing lactam head groups to the aminopyrazole hinge binding moiety. The corresponding analogues represent the most kinase selective ATP-competitive Group I PAK inhibitors described to date. Hydrogen bonding with the Thr-406 side chain was demonstrated by X-ray crystallography, and inhibitory activities, particularly against kinases with hydrophobic pre-DFG residues, were mitigated. Leveraging hydrogen bonding side chain interactions with polar pre-DFG residues is unprecedented, and similar strategies should be applicable to other appropriate kinases.
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Joachim
authors.initials: J
authors.lastname: Rudolph
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Crawford
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Simon
authors.initials: S
authors.lastname: Mathieu
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Wendy
authors.initials: W
authors.lastname: Lee
authors.affiliation: Shanghai Chempartner, Inc. , 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chao
authors.affiliation: Shanghai Chempartner, Inc. , 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Dong
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rouge
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heise
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Lesley J
authors.initials: LJ
authors.lastname: Murray
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Hank
authors.initials: H
authors.lastname: La
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Yanzhou
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Gerard
authors.initials: G
authors.lastname: Manning
authors.affiliation: ETH Zürich , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Diederich
authors.affiliation: Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
keywords: PAK1 kinase; Pre-DFG residue; aminopyrazole