AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies.
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G1-DNA damage checkpoint pathway resulting in reliance on S and G2 checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.
Zabludoff
Sonya D
SD
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. sonya.zabludoff@astrazeneca.com
Deng
Chun
C
Grondine
Michael R
MR
Sheehy
Adam M
AM
Ashwell
Susan
S
Caleb
Benjamin L
BL
Green
Stephen
S
Haye
Heather R
HR
Horn
Candice L
CL
Janetka
James W
JW
Liu
Dongfang
D
Mouchet
Elizabeth
E
Ready
Shannon
S
Rosenthal
Judith L
JL
Queva
Christophe
C
Schwartz
Gary K
GK
Taylor
Karen J
KJ
Tse
Archie N
AN
Walker
Graeme E
GE
White
Anne M
AM
D000818:Animals; D001681:Biological Assay; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D013876:Thiophenes / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D019772:Topotecan / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D047428:Protein Kinase Inhibitors; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D019772:Topotecan; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D000093542:Gemcitabine