Abstract A124: Discovery of the clinical candidate AZD1390: a high-quality, potent, and selective inhibitor of ATM kinase with the ability to cross the blood-brain barrier

Abstract

Abstract Glioblastoma multiforme (GBM) is the most common and lethal form of primary brain tumor, and current treatment (surgery followed by fractionated radiotherapy and temozolomide) provides a median survival of just 12-15 months (1,2). The poor prognosis associated with GBM is attributed to an extensive infiltration into surrounding brain tissue (thereby limiting the effectiveness of surgical excision), an intrinsic chemo/radioresistance of the tumor, and the presence of the blood-brain barrier (BBB), which limits the ability of certain chemotherapies to reach the tumor. Ataxia telangiectasia mutant (ATM) is a serine/threonine protein kinase from the phosphatidylinositol 3-kinase-related kinase (PIKK) family of protein kinases and plays a crucial role in the cellular DNA damage response signalling activated by DNA double-strand breaks (DSB). Activated ATM promotes DNA repair and S/G1-cell cycle checkpoints to prevent premature mitosis, maintain genomic integrity, and promote appropriate cell survival or death pathways. DSBs arise intrinsically through the collapse of stalled replication forks, which are induced by a wide range of chemotherapies, or extrinsically through exposure to ionizing radiation. Therefore, ATM inhibition represents an exciting clinical opportunity as a target to hyper-sensitize tumors to chemo/radiotherapy. The optimization of compound properties suitable to allow efficient BBB penetration remains a significant challenge within Medicinal Chemistry, and failure to consider these can severely restrict the utility of an agent for CNS disease. Herein, we describe the identification of AZD1390, a first-in-class orally available and CNS penetrant ATM inhibitor suitable for the treatment of intracranial malignancies. This presentation represents the first disclosure of the Medicinal Chemistry strategies employed to optimize BBB penetration, alongside the SAR for ATM potency, selectivity, and pharmacokinetic properties. AZD1390 is an exceptionally potent inhibitor of ATM in cells (IC50 = 0.78 nM) with >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases. AZD1390 displays excellent oral bioavailability in preclinical species (66% in rat and 74% in dog), is not a substrate for human efflux transporters, and has been shown to efficiently cross the BBB in non-human primate PET studies. Profound tumor regressions and increased animal survival (>50 days) have been observed in orthotopic xenograft models of brain cancer following just 2 or 4 days combination treatment of AZD1390 with radiotherapy, compared to radiotherapy treatment alone. These data support the potential of CNS-penetrant ATM inhibitors to provide an important new therapeutic agent for the treatment of intracranial malignancies. AZD1390 is currently undergoing early clinical assessment.