4iq6 Citations

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.

Reviews citing this publication (2)

  1. Recent advances of pyrrolopyridines derivatives: a patent and literature review. El-Gamal MI, Anbar HS. Expert Opin Ther Pat 27 591-606 (2017)
  2. Recent advances of pyrrolopyridines derivatives: a patent and literature review. El-Gamal MI, Anbar HS. Expert Opin Ther Pat 27 591-606 (2017)

Articles citing this publication (4)

  1. The optimization of aminooxadiazoles as orally active inhibitors of Cdc7. Harrington PE, Bourbeau MP, Fotsch C, Frohn M, Pickrell AJ, Reichelt A, Sham K, Siegmund AC, Bailis JM, Bush T, Escobar S, Hickman D, Heller S, Hsieh F, Orf JN, Rong M, San Miguel T, Tan H, Zalameda L, Allen JG. Bioorg. Med. Chem. Lett. 23 6396-6400 (2013)
  2. Synthesis and biological evaluation of pyrrolo[2,3-b]pyridine analogues as antiproliferative agents and their interaction with calf thymus DNA. Narva S, Chitti S, Bala BR, Alvala M, Jain N, Kondapalli VG. Eur J Med Chem 114 220-231 (2016)
  3. Leveraging the Pre-DFG Residue Thr-406 To Obtain High Kinase Selectivity in an Aminopyrazole-Type PAK1 Inhibitor Series. Rudolph J, Aliagas I, Crawford JJ, Mathieu S, Lee W, Chao Q, Dong P, Rouge L, Wang W, Heise C, Murray LJ, La H, Liu Y, Manning G, Diederich F, Hoeflich KP. ACS Med Chem Lett 6 711-715 (2015)
  4. Discovery of novel furanone derivatives as potent Cdc7 kinase inhibitors. Irie T, Asami T, Sawa A, Uno Y, Hanada M, Taniyama C, Funakoshi Y, Masai H, Sawa M. Eur J Med Chem 130 406-418 (2017)