Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper

Abstract

Purpose: We hypothesized that inhibition and trapping of Results: AZD5305 is a highly potent and selective inhibitor PARP1 alone would be sufficient to achieve antitumor activity. of PARP1 with 500-fold selectivity for PARP1 over PARP2. In particular, we aimed to achieve selectivity over PARP2, AZD5305 inhibits growth in cells with deficiencies in DNA repair, which has been shown to play a role in the survival of with minimal/no effects in other cells. Unlike first-generation hematopoietic/stem progenitor cells in animal models. We PARPi, AZD5305 has minimal effects on hematologic parameters developed AZD5305 with the aim of achieving improved clinin a rat pre-clinical model at predicted clinically efficacious expoical efficacy and wider therapeutic window. This nextsures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg generation PARP inhibitor (PARPi) could provide a paradigm once daily achieved greater depth of tumor regression compared to shift in clinical outcomes achieved by first-generation PARPi, olaparib 100 mg/kg once daily, and longer duration of response. particularly in combination. Conclusions: AZD5305 potently and selectively inhibits PARP1 Experimental Design: AZD5305 was tested in vitro for PARylaresulting in excellent antiproliferative activity and unprecedented selection inhibition, PARP-DNA trapping, and antiproliferative abilities. tivity for DNA repair deficient versus proficient cells. These data confirm In vivo efficacy was determined in mouse xenograft and PDX the hypothesis that targeting only PARP1 can retain the therapeutic models. The potential for hematologic toxicity was evaluated in benefit of nonselective PARPi, while reducing potential for hematorat models, as monotherapy and combination. toxicity. AZD5305 is currently in phase I trials (NCT04644068).