Mechanism of action: Ataxia Telangiectasia and Rad3 related (ATR) serine/threonine protein kinase inhibitor
AZD6738 is an ATP competitive, orally bioavailable inhibitor of the Serine/Threonine protein kinase Ataxia Telangiectasia and Rad3 related (ATR). It inhibits ATR with an in vitro enzyme IC50 of 0.001µM and inhibition of ATR substrate CHK1 Ser345 phosphorylation in cells at IC50 of 0.074µM. Changes is S-phase accumulation, impairment cell cycle progression and increases in pan-nuclear γH2AX DNA damage/replication stress markers are typically observed in 0.3-1.0µM range.
AZD6738 shows a good margin of selectivity against other kinases in broad in vitro assay screens (0/442 kinases show >50% inhibition at 1µM) and no significant inhibition of other PI3K-like kinases DNA-PK, ATM, mTOR or AKT with IC50 >5µM in cells.
AZD6738 monotherapy inhibited the proliferation of 73/197 solid and haematological cell lines with an IC50 of less than 1µM in 3 day proliferation assays. Enhanced sensitivity is observed, but is not restricted to, cell lines with loss of ATM function. In xenograft studies in vivo AZD6738 showed a dose-dependent modulation CHK1 phosphorylation and increase in pan-nuclear γH2AX staining. Chronic daily oral dosing as monotherapy showed significant dose-dependent tumour growth inhibition against several ATM-deficient but not ATM-proficient xenograft models.
AZD6738 showed synergistic cell killing activity when used in combination with either DNA damaging chemotherapy agents such as cisplatin, carboplatin, gemcitabine and bendamustine or ionising radiation (IR) across multiple cell lines. Significant enhancement of anti-tumour activity is observed in xenograft studies in vivo when AZD6738 is combined with either IR or carboplatin compared to monotherapies alone.