PARP inhibitors are effective in the treatment of homologous recombination repair deficient (HRD) tumors, such as those harboring a BRCA mutation (BRCAm), and have attracted a considerable amount of research interest. Recently there have been numerous activities exploring the use of PARP inhibitors in the CNS, which could have benefits in a number of indications such as: 1) BRCAm tumors with a high propensity for brain metastasis, such as breast cancer, 2) glioblastoma and other CNS malignancies with elevated baseline replication stress and constitutive DNA damage response pathway (DDR) activation, and 3) neurological conditions. AstraZeneca has previously described the discovery of a next generation PARP1 selective inhibitor and PARP1-DNA trapper, AZD5305, which was not designed for CNS penetration. In this work we sought to retain its benefits while optimizing for low efflux and high CNS exposure. Using structure- and property-based design, we were able to reduce efflux through changes to the nicotinamide mimetic core as well as masking hydrogen bond donors. AZD9574 is a potent inhibitor of PARP1 and is selective over the closely related PARP2 and the other members of the PARP family as demonstrated by in vitro binding assays and PARP affinity proteomics. It has shown low efflux in Caco2, MDCK-MDR1, and MDCK-MDR1-BCRP permeability assays. Congruent with this, AZD9574 has demonstrated CNS penetration in rat and cynomolgus monkey. In vitro, AZD9574 selectively inhibits the growth of BRCAm cell lines, and in isogenic cell line pairs, shows superior selectivity towards HRD cancer cells. The compound is a potent inhibitor of PARylation and demonstrates no effect on PARylation in PARP1 knock-out cells, consistent with very high specificity for PARP1. AZD9574 demonstrates PARP1-DNA trapping but not PARP2 trapping. Importantly, AZD9574 showed efficacy in an intracranial BRCA1m MDA-MB-436 xenograft model at doses of 3, 10 and 30 mg/kg QD, significantly extending the survival of tumor-bearing mice compared to vehicle control arm. AZD9574 is a next generation PARP inhibitor and trapper with CNS penetration. This profile makes it an ideal candidate for treating CNS malignancies or brain metastases that have a dependence on PARP inhibition either as single agent or in combination with other therapies. AZD9574 will soon enter clinical trials.

Discovery and first structural disclosure of AZD9574, a CNS penetrant PARP1 selective inhibitor

ACS Spring 2022

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