DDDR-01. Azd9574 Is a Novel, Brain Penetrant Parp-1 Selective Inhibitor With Activity in an Intracranial Xenograft Model of Triple Negative Breast Carcinoma With Homologous Recombination Repair Deficiency

Abstract

The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)

Advances in Development of Selective Antitumor Inhibitors That Target PARP-1

“…Given the substantial homology between the catalytic domains of PARP-1 and PARP-2 proteins, the task of developing selective PARP-1 inhibitors is indeed challenging. However, significant differences can be found in the other domains of PARP-1 and PARP-2, including the absence of both BRCT (in the AMD domain) and a ZF (in the DBD) that acts as a gap sensor in PARP-2; these differences are responsible for the differences in the functions of PARP-1 and PARP-2, and provide scope for the development of selective PARP-1 inhibitors. , In fact, the past two decades have witnessed the gradual discovery of selective PARP-1 inhibitors; while selective PARP-1 inhibitors have not been approved for clinical use and marketing to date, two highly selective and potent PARP-1 inhibitors, AZD5305 (compound 37 ) and AZD9574 (compound 38 ) are currently undergoing clinical trials. , The extensive search for selective PARP-1 inhibitors and efforts to understand the mechanisms underlying their selectivity have led to the discovery of several classes of molecules that exhibit selectivity, including quinazolinones, isoquinolinones, isoindolinones, bromophenols, apigenins, and lactams.…”

“…Compound 38 is the second selective PARP-1 inhibitor from AstraZeneca, the first being compound 37 . Compared with its predecessor, compound 38 is unique in exhibiting central nervous system penetration, which allows it to potentially target primary and secondary brain malignancies.…”

“…48,49 In fact, the past two decades have witnessed the gradual discovery of selective PARP-1 inhibitors; while selective PARP-1 inhibitors have not been approved for clinical use and marketing to date, two highly selective and potent PARP-1 inhibitors, AZD5305 (compound 37) and AZD9574 (compound 38) are currently undergoing clinical trials. 11,50 The extensive search for selective PARP-1 inhibitors and efforts to understand the mechanisms underlying their selectivity have led to the discovery of several classes of molecules that exhibit selectivity, including quinazolinones, isoquinolinones, isoindolinones, bromophenols, apigenins, and lactams.…”

“…Compound 38 is the second selective PARP-1 inhibitor from AstraZeneca, the first being compound 37. 11 Compared with its predecessor, compound 38 is unique in exhibiting central nervous system penetration, which allows it to potentially target primary and secondary brain malignancies. In biochemical assays, compound 38 exhibited greater than 8000-fold selectivity for PARP-1 over PARP-2 and other PARP family members (PARP-3, PARP-5a, and PARP-6), and it also inhibited the enzymatic activity of PARP-1 in all cell lines tested; in fact, compound 38 exhibited greater potency and selectivity in the HRD + model.…”

“…Recent studies have shown that inhibition of PARP-1 is sufficient for exerting an antiproliferative effect on tumor cells, while PARP-2 function is critical for the survival of progenitor and hematopoietic stem cells in animal models. 11 Therefore, improving the selectivity of PARP-1 inhibitors not only achieves antitumor effects but also helps in reducing the toxic effects associated with PARP-2 inhibition. As a result, improvement in selectivity and the development of selective inhibitors with high activity has become the focus and main direction for the development of a new generation of PARP inhibitors.…”