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ACS Med Chem Lett. 2013 Jan 15;4(2):211-5. doi: 10.1021/ml300348c. eCollection 2013 Feb 14.

Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195.

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Cancer Research, Structural Biology, Lead Discovery, and Protein Biochemistry, Global Pharmaceutical Research and Development, Abbott Laboratories , 100 Abbott Park Road, Abbott Park, Illinois 60064, United States.


To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3β, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.


Cdc7 kinase; azaindole; pre-DFG residue

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