Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors.
Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG U. K.
Michael
M
Lainchbury
Thomas P
TP
Matthews
Tatiana
T
McHardy
Kathy J
KJ
Boxall
Michael I
MI
Walton
Paul D
PD
Eve
Angela
A
Hayes
Melanie R
MR
Valenti
Alexis K
AK
de Haven Brandon
Gary
G
Box
G Wynne
GW
Aherne
John C
JC
Reader
Florence I
FI
Raynaud
Suzanne A
SA
Eccles
Michelle D
MD
Garrett
Ian
I
Collins
D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D002648:Child; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004249:DNA Damage / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology; D009687:Nuclear Proteins / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C577959:3-((1-(dimethylamino)propan-2-yl)oxy)-5-((4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)amino)pyrazine-2-carbonitrile; D000631:Aminopyridines; D000970:Antineoplastic Agents; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse