title: Azaindole-Based Inhibitors of Cdc7 Kinase: Impact of the Pre-DFG Residue, Val 195.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yunsong
authors.initials: Y
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.affiliation: 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.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Florjancic
authors.affiliation: 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.
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.affiliation: 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.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.affiliation: 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.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Przytulinska
authors.affiliation: 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.
authors.forename: Nirupama
authors.initials: N
authors.lastname: Soni
authors.affiliation: 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.
authors.forename: Kerren K
authors.initials: KK
authors.lastname: Swinger
authors.affiliation: 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.
authors.forename: Haizhong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shoemaker
authors.affiliation: 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.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Penning
keywords: Cdc7 kinase; azaindole; pre-DFG residue