The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one)

Abstract

ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of 7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo[4,5- c]quinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.

BK Polyomavirus Activates the DNA Damage Response To Prolong S Phase

“…Similar results were obtained using structurally different inhibitors of ATR and ATM to rule out off-target or nonspecific effects from using a single set of DDR inhibitors ( Fig. 3J and K) (25,26). These findings suggest that activation of both ATR and ATM is required synergistically to prevent progression from S phase during BKPyV infection ( Fig.…”

EVI1 carboxy-terminal phosphorylation is ATM-mediated and sustains transcriptional modulation and self-renewal via enhanced CtBP1 association

“…This novel aspect of EVI1 function, in particular with respect to transformation and self-renewal, is therapeutically relevant for EVI1-overexpressing malignancies, as chemotherapy induced genotoxicity might detrimentally sustain EVI1 function. Inhibition of ATM with an orally applicable compound (51) is currently subject to phase 1 clinical evaluation and has shown activity in a murine leukaemia model (52). ATM inhibition or therapeutic interference of the enhanced EVI1 interaction with CtBP1 after genotoxic stress might be of particular benefit in EVI1 overexpressing malignancies, and this will be subject to further work.…”

Pharmacology of the ATM Inhibitor AZD0156: Potentiation of Irradiation and Olaparib Responses Preclinically

“…AZD0156 was discovered after chemical optimization of a novel series of ATM inhibitors resulting in a highly significant increase in both potency and selectivity, while also delivering a compound with good physicochemical properties, good preclinical pharmacokinetic profiles, and an acceptable predicted clinically efficacious dose (ref. 21; Fig. 1C).…”

“…Compounds (AZD0156 and olaparib) were synthesized internally at AstraZeneca laboratories (21) and dissolved in 100% DMSO at 1 mmol/L (AZD0156) or 10 mmol/L (olaparib) stocks, which were used for in vitro studies.…”

“…17,18). The activity of PARP inhibitors in BRCAmut tumors exploits the principle of synthetic lethality (19), and preclinical studies indicate that PARP synthetic lethal interactions extend beyond BRCA to DDR proteins including ATM (20)(21)(22). Consequently, inhibition of ATM is anticipated to potentiate the effects of PARP inhibitors in the clinic.…”