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ACS Med Chem Lett. 2015 May 20;6(6):711-5. doi: 10.1021/acsmedchemlett.5b00151. eCollection 2015 Jun 11.

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

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Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
Shanghai Chempartner, Inc. , 998 Halei Road, Zhangjiang Hi-Tech Park, Pudong New Area, Shanghai 201203, People's Republic of China.
ETH Zürich , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.


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.


PAK1 kinase; Pre-DFG residue; aminopyrazole

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