Abstract ND05: Discovery and first structural disclosure of AZD5305: A next generation, highly selective PARP1 inhibitor and trapper

Abstract

Poly ADP-ribose polymerase (PARP) inhibitors have demonstrated clinical effectiveness in the treatment of homologous recombination deficient tumors; however, hematological and other toxicities have limited their use as a class of agents, both as monotherapy and as combination with already poorly tolerated chemotherapies. Recent literature suggests that inhibition of PARP2, a feature shared by all the current clinical PARP inhibitors, is not required for efficacy and may in fact be associated with hematological effects. These observations led to our hypothesis that a highly selective and potent PARP1 inhibitor and trapper would retain efficacy while improving therapeutic index, thus expanding clinical combinations options. A high throughput screen against PARP1 and PARP2 identified a compound series with selectivity for binding to PARP1 over PARP2. This set of compounds was refined further by screening for the ability to trap PARP1 to DNA and selectively inhibit growth of BRCA mutant cell lines. Further lead optimization efforts utilizing PARP1 enzyme structural information, lead to the discovery of to AZD5305. AZD5305 is a highly potent inhibitor of PARP1, with significant PARP1-DNA trapping activity, no PARP2-activity, nor binding activity to any other members of the PARP family. AZD5305 has excellent secondary pharmacology and physicochemical properties as well as high oral bioavailability in preclinical species. AZD5305 has shown unique properties in preclinical toxicology models. When dosed daily for 14 days in rats at clinically equivalent doses, olaparib (a PARP1/2 inhibitor), causes up to 50% reduction in hemoglobin, in line with clinically observed anemia. Under the same experimental conditions, AZD5305 had no effects on any hematological parameters measured, when dosed at predicted clinically efficacious doses. In vitro, AZD5305 inhibits growth selectively in cell lines with deficiencies in DNA repair pathways, with IC50s in the single-digit nM range, while having no or minimal growth inhibitory effects in other cells (IC50s >10μM). The difference observed between the effects on DNA repair deficient and proficient cell lines is unprecedented with PARP inhibitors and indicates the great potential for AZD5305 to demonstrate an improved therapeutic index in the clinic. Treatments of xenografts and PDX models with AZD5305 at doses ≥ 0.1 mg/kg QD, compared to olaparib 100 mg/kg QD, resulted in greater depth of tumor regressions, as well as significantly longer duration of regressions following cessation of dosing. Overall, AZD5305 is a next generation PARP inhibitor and trapper, with enhanced anticancer efficacy and an improved safety profile in preclinical models compared to other PARP inhibitors. These features make AZD5305 an exciting and unique clinical candidate, with multiple clinical options as monotherapy and in combination. AZD5305 is in Ph1 clinical trials. Citation Format: Elisabetta Leo, Jeffrey Johannes. Discovery and first structural disclosure of AZD5305: A next generation, highly selective PARP1 inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr ND05.