2wmx Citations

Identification of inhibitors of checkpoint kinase 1 through template screening.

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 - 2wmx 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)