Abstract 6302: Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper

Abstract

PARP inhibitors exploit defects in DNA repair pathways to selectively target cancerous cells via PARP1 catalytic inhibition and PARP1 trapping onto the DNA. All known clinical PARP1 inhibitors bind at the same site at the catalytic center of the enzyme. However, despite this resemblance they show immensely different outcomes in terms of response rate in the clinic due to their varying degree of PARP trapping ability. Moreover, the first-generation PARP inhibitors were not optimized for selectivity across the PARP family potentially driving undesirable side effects, including intestinal toxicity from tankyrase inhibition or hematological toxicity from PARP2 inhibition. There has been strong rationale for the use of PARP inhibitors in neuro-oncology. However, the first-generation PARP inhibitors have limited CNS distribution as these drugs were not designed for brain penetration. Recently AstraZeneca has reported the discovery of AZD5305, a next generation PARP1 selective inhibitor and PARP1-DNA trapper which was not designed with a CNS penetrant profile. Given the unmet need of a brain penetrant PARP1 inhibitor, we set out to identify a highly potent and selective PARP1 inhibitor and trapper with CNS profile. In our next generation PARP1 inhibitor, we sought to retain the profile of AZD5305 and lower the efflux for CNS penetration. Despite the challenge of narrow SAR, we successfully used the structure- and property-based design approach to identify a brain penetrant PARP1 inhibitor and PARP1-DNA trapper. We used multiple medicinal chemistry maneuvers such as masking the hydrogen bond donors and core modifications to lower the efflux in order to achieve brain penetration. Further optimization of the nicotinamide mimetic core for potency and metabolic stability led us to the discovery of AZD9574.AZD9574 shows improved selectivity for PARP1 over PARP2 vs AZD5305 and retains its excellent selectivity over other PARP family members. It has low efflux in Caco2, MDCK-MDR1, and MDCK-MDR1-BCRP permeability assays and it also showed CNS penetration in rat and cynomolgus monkey. AZD9574 has excellent secondary pharmacology and acceptable physicochemical properties and good PK in preclinical species.In vitro, AZD9574 selectively inhibits the growth of BRCAm cell lines. 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.In summary, AZD9574 is a next generation selective PARP1 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. Citation Format: Avipsa Ghosh, Sudhir M. Hande, Amber Balazs, Derek Barratt, Sabina Cosulich, Barry Davies, Sébastien Degorce, Kevin Embrey, Sonja Gill, Anders Gunnarsson, Giuditta Illuzzi, Peter Johnström, Jordan Lane, Carrie Larner, Rachel Lawrence, Elisabetta Leo, Andrew Madin, Elizabeth Martin, Lisa McWilliams, Lenka O’Connor, Mark O’Connor, Jonathan Orme, Fiona Pachl, Martin Packer, Andy Pike, Philip Rawlins, Marianne Schimpl, Magnus Schou, Anna Staniszewska, Wenzhan Yang, James Yates, Andrew Zhang, XiaoLa Zheng, Stephen Fawell, Petra Hamerlik, Jeffrey Johannes. Structure-based and property-based drug design of AZD9574, a CNS penetrant PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6302.

New Horizons of Synthetic Lethality in Cancer: Current Development and Future Perspectives

“…In its latest generation of PARP1 inhibitors, AstraZeneca managed to lower efflux for CNS penetration by masking hydrogen bond (HB) donors and introducing core modifications, resulting in the development of AZD9574 (Figure ). This molecule represents the first brain penetrant PARP1 selective inhibitor (PARP1 IC 50 < 0.005 μM, and PARP1/2 selectivity fold > 19 107) and PARP1-DNA trapping agent in clinical trials (NCT05417594) …”

“…This molecule represents the first brain penetrant PARP1 selective inhibitor (PARP1 IC 50 < 0.005 μM, and PARP1/2 selectivity fold > 19 107) and PARP1-DNA trapping agent in clinical trials (NCT05417594). 41 …”

“…This molecule represents the first brain penetrant PARP1 selective inhibitor (PARP1 IC 50 < 0.005 μM, and PARP1/2 selectivity fold > 19 107) and PARP1-DNA trapping agent in clinical trials (NCT05417594). 41 Concurrently with the advancement of PARP1 inhibitors, it is necessary to mention the controversial studies emerging about previously unexpected toxicity in normal tissues. These include evidence of toxicity in human healthy bone marrow cells, 42 linked to the trapping activity of PARP1 inhibitors, and the embryonic lethality due to PARP1 loss in a dominantnegative manner in a mouse model.…”