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

Tong Y, Stewart KD, Florjancic AS, Harlan JE, Merta PJ, Przytulinska M, Soni N, Swinger KK, Zhu H, Johnson EF, Shoemaker AR, Penning TD
ACS Med Chem Lett 4 211-5 (2013)
Cited: 15 times
EuropePMC logo PMID: 24900653

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 - 4iq6 mentioned but not cited (1)

  1. The azaindole framework in the design of kinase inhibitors. Mérour JY, Buron F, Plé K, Bonnet P, Routier S. Molecules 19 19935-19979 (2014)

Articles - 4iq6 mentioned but not cited (5)

  1. Molecular docking based screening analysis of GSK3B. Ogunleye AJ, Olanrewaju AJ, Arowosegbe M, Omotuyi OI. Bioinformation 15 201-208 (2019)
  2. ARN25068, a versatile starting point towards triple GSK-3β/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders. Demuro S, Sauvey C, Tripathi SK, Di Martino RMC, Shi D, Ortega JA, Russo D, Balboni B, Giabbai B, Storici P, Girotto S, Abagyan R, Cavalli A. Eur J Med Chem 229 114054 (2022)
  3. Naphthoquinone as a New Chemical Scaffold for Leishmanicidal Inhibitors of Leishmania GSK-3. Sebastián-Pérez V, Martínez de Iturrate P, Nácher-Vázquez M, Nóvoa L, Pérez C, Campillo NE, Gil C, Rivas L. Biomedicines 10 1136 (2022)
  4. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)
  5. Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3β and Tau Aggregation with Potential Neuroprotective Activity. Ali TFS, Ciftci HI, Radwan MO, Roshdy E, Shawky AM, Abourehab MAS, Tateishi H, Otsuka M, Fujita M. Pharmaceuticals (Basel) 15 426 (2022)


Reviews citing this publication (1)

  1. 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 (8)

  1. Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Wells CI, Drewry DH, Pickett JE, Tjaden A, Krämer A, Müller S, Gyenis L, Menyhart D, Litchfield DW, Knapp S, Axtman AD. Cell Chem Biol 28 546-558.e10 (2021)
  2. Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity. Yang C, Zhang X, Wang Y, Yang Y, Liu X, Deng M, Jia Y, Ling Y, Meng LH, Zhou Y. ACS Med Chem Lett 8 875-880 (2017)
  3. 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)
  4. 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)
  5. 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)
  6. Receptor-based pharmacophore modeling, virtual screening, and molecular docking studies for the discovery of novel GSK-3β inhibitors. El Kerdawy AM, Osman AA, Zaater MA. J Mol Model 25 171 (2019)
  7. 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)
  8. A Structural and In Silico Investigation of Potential CDC7 Kinase Enzyme Inhibitors. Mookkan M, Kandasamy S, Al-Odayni AB, Abduh NAY, Srinivasan S, Revannasidappa BC, Kumar V, Chinnasamy K, Aravindhan S, Shankar MK. ACS Omega 8 47187-47200 (2023)


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