CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors.
CHK2 is a checkpoint kinase involved in the ATM-mediated response to double-strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC(50) of 3 nmol/L and shows minimal cross-reactivity against a panel of kinases at 1 μmol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors.
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Victoria E
VE
Anderson
Michael I
MI
Walton
Paul D
PD
Eve
Katherine J
KJ
Boxall
Laurent
L
Antoni
John J
JJ
Caldwell
Wynne
W
Aherne
Laurence H
LH
Pearl
Antony W
AW
Oliver
Ian
I
Collins
Michelle D
MD
Garrett
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001761:Bleomycin / Q000008:administration & dosage; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
C556313:4-fluoro-2-(4-(4-(2-hydroxypropan-2-yl)pyrrolidin-3-ylamino)-6,7-dimethoxyquinazolin-2-yl)phenol; C520469:AG14447; D006575:Heterocyclic Compounds, 3-Ring; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D001761:Bleomycin; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases
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