ATR inhibitor AZD6738

AZD6738 is a potent and selective orally bio-available inhibitor of ataxia telangiectasia and rad3 related (ATR),a key serine/threonine protein kinase involved in DNA damage response signalling caused by DNA replication associated stress. Activation of ATR at stalled replication forks leads to suppression of replication fork origin firing, promotes repair and activates S/G1/G2-cell cycle checkpoints to prevent premature mitosis and maintain genomic integrity. Failure to resolve this damage leads to genomic instability and if sufficiently high, cell death. Cancer cells undergoing high levels of replication associated DNA damage or in cells with deficiencies in ATM-dependent repair pathways are hypothesised to be more reliant on ATR for survival and specific inhibition of ATR may lead to enhanced anti-tumour activity. In patients with malignant disease, an ATR inhibitor has the potential to: • Have monotherapy activity, through synthetic lethality or by exploiting on-going aberrant DNA replication structures leading to dependency on ATR • Act synergistically in combination with DNA damaging therapies, either systemic therapies or a localised DNA damaging therapy, such as radiotherapy which activate ATR • Act as a maintenance therapeutic after either of the above. AZD6738 monotherapy response across cell line panels in vitro shows a wide range of sensitivities and is well tolerated at efficacious doses in vivo. ATM-deficient cells are enriched for greater sensitivity to AZD6738 which offers a potential testable patient selection hypothesis. However, AZD6738 also shows enhanced activity in some (but not all) ATM-proficient cells such those from haematological malignancies. In addition, combination of AZD6738 with radiation induces regression in both ATM-deficient and ATM-proficient models (albeit at different AZD6738 doses). Anti-tumour activity of AZD6738 may, therefore, also be seen more broadly than ATM-deficiency particularly in combinations. Here we describe the 2 clinical studies with AZD6738 that will test the monotherapy and combination therapy (potentiation of DNA damage) hypotheses, along with an overview of the pre-clinical in vitro and in vivo data supporting this.