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Published on: August 21, 2013
Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper
Giuditta Illuzzi1, Anna D Staniszewska1, Sonja J Gill2
1Bioscience, Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Purpose:
We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination.
Experimental Design:
AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination.
Results:
AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response.
Conclusions:
AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
Insights
A new drug, AZD5305, selectively targets PARP1, showing strong antitumor activity with less toxicity than older drugs. This PARP inhibitor offers a potential improvement in cancer treatment, especially when used in combination therapies.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Poly(ADP-ribose) polymerase inhibitors (PARPi) are crucial in cancer therapy, particularly for tumors with DNA repair deficiencies.
- First-generation PARPi can cause hematologic toxicity due to PARP2 inhibition, limiting their therapeutic window.
- Developing PARP1-selective inhibitors aims to enhance efficacy and reduce side effects.
Purpose of the Study:
- To evaluate AZD5305, a novel PARP inhibitor designed for potent and selective PARP1 inhibition.
- To assess the antitumor activity and therapeutic window of AZD5305 compared to existing PARPi.
- To investigate the potential for reduced hematologic toxicity with PARP1-selective inhibition.
Main Methods:
- In vitro assays for PARylation inhibition, PARP-DNA trapping, and antiproliferative effects.
- In vivo studies using mouse xenograft and patient-derived xenograft (PDX) models.
- Pre-clinical evaluation of hematologic toxicity in rat models.
Main Results:
- AZD5305 demonstrated high potency and selectivity for PARP1 over PARP2 (500-fold).
- Significant inhibition of cancer cell growth was observed in DNA repair-deficient cells.
- AZD5305 showed superior tumor regression and longer response duration compared to olaparib in animal models.
- Minimal hematologic toxicity was observed in pre-clinical models at efficacious doses.
Conclusions:
- AZD5305 potently and selectively inhibits PARP1, leading to significant antitumor activity.
- Targeting PARP1 alone retains therapeutic benefits while potentially reducing hematotoxicity.
- AZD5305 represents a promising next-generation PARPi with a potentially wider therapeutic window, currently in Phase I clinical trials.
