Identification of inhibitors of checkpoint kinase 1 through template screening.
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.
Matthews
Thomas P
TP
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
Klair
Suki
S
Burns
Samantha
S
Boxall
Kathy
K
Cherry
Michael
M
Fisher
Martin
M
Westwood
Isaac M
IM
Walton
Michael I
MI
McHardy
Tatiana
T
Cheung
Kwai-Ming J
KM
Van Montfort
Rob
R
Williams
David
D
Aherne
G Wynne
GW
Garrett
Michelle D
MD
Reader
John
J
Collins
Ian
I
D000071877:Checkpoint Kinase 1; D004353:Drug Evaluation, Preclinical; D019073:HT29 Cells; D006801:Humans; D006860:Hydrogen Bonding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1