NU6027 is a potent inhibitor of cellular ATR activity with the IC50 of 6.7 μM.
The ataxia telangiectasia mutated and Rad3-related kinase (ATR) has a crucial role in the stalled replication forks signalling and DNA damage to cell cycle checkpoints and DNA repair. ATR was recognised as an key target for cancer therapy, however, its inhibitors have proved elusive. NU6027, which was originally developed as a CDK2 inhibitor, inhibits ATR.
In vitro: NU6027 is a potent inhibitor of cellular ATR activity with the IC50 of 6.7 μM and enhanced the cytotoxicity of hydroxyurea and cisplatin in an ATR-dependent manner. NU6027 attenuated G2/M phase arrest with DNA damage, inhibited the formation of RAD51 focus and increased the cytotoxicity of the major classes of DNA-damaging cytotoxic therapy but not paclitaxel and antimitotic. In A2780 cells, cisplatin sensitisation was greatest in cells with functional p53 and mismatch repair and sensitisation to temozolomide was greatest in p53 mutant cells with functional mismatch repair. More importantly, NU6027 was found to be synthetically lethal when DNA single-strand break repair is impaired either through poly(ADP-ribose) polymerase (PARP) inhibition or defects in XRCC1 [1].
In vivo: Currently no in-vivo data are available.
Clinical trial: NU6027 is still in preclinical development stage and no clinicl trial is ongoing currently.
Reference:
[1] Peasland A, Wang LZ, Rowling E, Kyle S, Chen T, Hopkins A, Cliby WA, Sarkaria J, Beale G, Edmondson RJ, Curtin NJ. Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines. Br J Cancer. 2011;105(3):372-81.