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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.

SUBMITTER: Rudolph J 

PROVIDER: S-EPMC4468403 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series.

Rudolph Joachim J   Aliagas Ignacio I   Crawford James J JJ   Mathieu Simon S   Lee Wendy W   Chao Qi Q   Dong Ping P   Rouge Lionel L   Wang Weiru W   Heise Christopher C   Murray Lesley J LJ   La Hank H   Liu Yanzhou Y   Manning Gerard G   Diederich François F   Hoeflich Klaus P KP  

ACS medicinal chemistry letters 20150520 6

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 demonstrat  ...[more]

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