Reference Detail

Ref Type

Journal Article

PMID

(35929986)

Authors

Illuzzi G, Staniszewska AD, Gill SJ, Pike A, McWilliams L, Critchlow SE, Cronin A, Fawell S, Hawthorne G, Jamal K, Johannes J, Leonard E, Macdonald R, Maglennon G, Nikkil J, O'Connor MJ, Smith A, Southgate H, Wilson J, Yates J, Cosulich S, Leo E

Title

Preclinical characterization of AZD5305, a next generation, highly selective PARP1 inhibitor and trapper.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2022 Aug 05	4724-4736	Clin Cancer Res

URL

Abstract Text

We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve anti-tumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to a play role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim to achieve improved clinical efficacy and wider therapeutic window. This next generation PARPi could provide a paradigm shift in clinical outcomes achieved by first generation PARPi, particularly in combination.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 hematological toxicity was evaluated in rat models as monotherapy and combination.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 hematological parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1mg/kg QD achieved greater depth of tumor regression compared to olaparib 100mg/kg QD, and longer duration of response.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 therapeutic benefits of non-selective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in Ph1 trials (NCT04644068).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AZD5305	AZD5305	2	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AZD5305		AZD 5305\|AZD-5305	PARP-1 Inhibitor 8	AZD5305 inhibits PARP1, potentially inhibiting cell growth and inducing tumor regression (PMID: 35929986).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PALB2 del	ovarian cancer	sensitive	AZD5305	Preclinical - Cell culture	Actionable	In a preclinical study, AZD5305 inhibited colony formation in an ovarian cancer cell line with PALB2 deletion in culture (PMID: 35929986).	35929986
RAD51C del	ovarian cancer	sensitive	AZD5305	Preclinical - Cell culture	Actionable	In a preclinical study, AZD5305 inhibited colony formation in an ovarian cancer cell line with RAD51C deletion in culture (PMID: 35929986).	35929986