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Identification of inhibitors of checkpoint kinase 1 through template screening.

Matthews TP, Klair S, Burns S, Boxall K, Cherry M, Fisher M, Westwood IM, Walton MI, McHardy T, Cheung KM, Van Montfort R, Williams D, Aherne GW, Garrett MD, Reader J, Collins I
J Med Chem 52 4810-9 (2009)
Related entries: 2wmq, 2wmr, 2wms, 2wmu, 2wmv, 2wmw, 2wmx

Cited: 18 times
EuropePMC logo PMID: 19572549

Abstract

Checkpoint kinase 1 (CHK1) is an oncology target of significant current interest. Inhibition of CHK1 abrogates DNA damage-induced cell cycle checkpoints and sensitizes p53 deficient cancer cells to genotoxic therapies. Using template screening, a fragment-based approach to small molecule hit generation, we have identified multiple CHK1 inhibitor scaffolds suitable for further optimization. The sequential combination of in silico low molecular weight template selection, a high concentration biochemical assay and hit validation through protein-ligand X-ray crystallography provided 13 template hits from an initial in silico screening library of ca. 15000 compounds. The use of appropriate counter-screening to rule out nonspecific aggregation by test compounds was essential for optimum performance of the high concentration bioassay. One low molecular weight, weakly active purine template hit was progressed by iterative structure-based design to give submicromolar pyrazolopyridines with good ligand efficiency and appropriate CHK1-mediated cellular activity in HT29 colon cancer cells.

Articles - 2wmt mentioned but not cited (1)

  1. Discovery of novel checkpoint kinase 1 inhibitors by virtual screening based on multiple crystal structures. Li Y, Kim DJ, Ma W, Lubet RA, Bode AM, Dong Z. J Chem Inf Model 51 2904-2914 (2011)


Reviews citing this publication (6)

  1. Structural biology in fragment-based drug design. Murray CW, Blundell TL. Curr Opin Struct Biol 20 497-507 (2010)
  2. Structure-based design, discovery and development of checkpoint kinase inhibitors as potential anticancer therapies. Matthews TP, Jones AM, Collins I. Expert Opin Drug Discov 8 621-640 (2013)
  3. Checkpoint kinase inhibitors: a patent review (2009 - 2010). Lainchbury M, Collins I. Expert Opin Ther Pat 21 1191-1210 (2011)
  4. In silico fragment-based drug design. Konteatis ZD. Expert Opin Drug Discov 5 1047-1065 (2010)
  5. Pyrazolo[3,4-b]pyridine kinase inhibitors: a patent review (2008--present). Wenglowsky S. Expert Opin Ther Pat 23 281-298 (2013)
  6. The hunt for antimitotic agents: an overview of structure-based design strategies. Dube D, Tiwari P, Kaur P. Expert Opin Drug Discov 11 579-597 (2016)

Articles citing this publication (11)

  1. Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. Schonbrunn E, Betzi S, Alam R, Martin MP, Becker A, Han H, Francis R, Chakrasali R, Jakkaraj S, Kazi A, Sebti SM, Cubitt CL, Gebhard AW, Hazlehurst LA, Tash JS, Georg GI. J Med Chem 56 3768-3782 (2013)
  2. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, Ruddle R, Henley A, de Haven Brandon A, Valenti M, Davies TG, Fazal L, Seavers L, Raynaud FI, Eccles SA, Aherne GW, Garrett MD, Collins I. J Med Chem 53 2239-2249 (2010)
  3. Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 1. Dwyer MP, Paruch K, Labroli M, Alvarez C, Keertikar KM, Poker C, Rossman R, Fischmann TO, Duca JS, Madison V, Parry D, Davis N, Seghezzi W, Wiswell D, Guzi TJ. Bioorg Med Chem Lett 21 467-470 (2011)
  4. Structure-guided evolution of potent and selective CHK1 inhibitors through scaffold morphing. Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I. J Med Chem 54 8328-8342 (2011)
  5. Fragment-based and structure-guided discovery and optimization of Rho kinase inhibitors. Li R, Martin MP, Liu Y, Wang B, Patel RA, Zhu JY, Sun N, Pireddu R, Lawrence NJ, Li J, Haura EB, Sung SS, Guida WC, Schonbrunn E, Sebti SM. J Med Chem 55 2474-2478 (2012)
  6. Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: a template-based approach--part 2. Labroli M, Paruch K, Dwyer MP, Alvarez C, Keertikar K, Poker C, Rossman R, Duca JS, Fischmann TO, Madison V, Parry D, Davis N, Seghezzi W, Wiswell D, Guzi TJ. Bioorg Med Chem Lett 21 471-474 (2011)
  7. Virtual Screening and Statistical Analysis in the Design of New Caffeine Analogues Molecules with Potential Epithelial Anticancer Activity. da Silva Costa J, da Silva Lopes Costa K, Cruz JV, da Silva Ramos R, Silva LB, Do Socorro Barros Brasil D, de Paula da Silva CHT, Dos Santos CBR, da Cruz Macedo WJ. Curr Pharm Des 24 576-594 (2018)
  8. Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases. Matthews TP, McHardy T, Klair S, Boxall K, Fisher M, Cherry M, Allen CE, Addison GJ, Ellard J, Aherne GW, Westwood IM, van Montfort R, Garrett MD, Reader JC, Collins I. Bioorg Med Chem Lett 20 4045-4049 (2010)
  9. Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. Lainchbury M, Matthews TP, McHardy T, Boxall KJ, Walton MI, Eve PD, Hayes A, Valenti MR, de Haven Brandon AK, Box G, Aherne GW, Reader JC, Raynaud FI, Eccles SA, Garrett MD, Collins I. J Med Chem 55 10229-10240 (2012)
  10. Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands-computational investigations. Czaja K, Kujawski J, Kamel K, Bernard MK. J Mol Model 26 144 (2020)
  11. Fragment-based screening maps inhibitor interactions in the ATP-binding site of checkpoint kinase 2. Silva-Santisteban MC, Westwood IM, Boxall K, Brown N, Peacock S, McAndrew C, Barrie E, Richards M, Mirza A, Oliver AW, Burke R, Hoelder S, Jones K, Aherne GW, Blagg J, Collins I, Garrett MD, van Montfort RL. PLoS One 8 e65689 (2013)


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