Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs

Abstract

Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1− DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure-and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1−DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.

Opinion: PARP inhibitors in cancer—what do we still need to know?

“…At present, biomarkers that predict dose-limiting toxicity do not exist. It seems possible that PARP1 trapping in myeloid cells explains (at least in part) the haematological toxicities seen with PARPi [ 45 , 87 ]. Given this, biomarkers that allow PARP1 trapping to be measured in patient samples might be of use and could predict those more likely to eventually show dose limiting toxicity before it occurs (e.g.…”

“…Additional PARPi (talazoparib (Pfizer), rucaparib (Clovis Oncology), niraparib (GlaxoSmithKline) and pamiparib (BeiGene) [ 44 ]) are also approved for the treatment of cancer, while others (e.g. AZD5305 (AstraZeneca) [ 45 ]) are still in clinical development. Future improvements to PARPi could include increased PARP1 specificity to circumvent off-target toxicity [ 45 ], decreased PgP efflux to decrease likelihood of this resistance mechanism [ 46 ] (see below) and modifications that increase tumour cell-selective PARP1 trapping [ 22 ].…”

“…AZD5305 (AstraZeneca) [ 45 ]) are still in clinical development. Future improvements to PARPi could include increased PARP1 specificity to circumvent off-target toxicity [ 45 ], decreased PgP efflux to decrease likelihood of this resistance mechanism [ 46 ] (see below) and modifications that increase tumour cell-selective PARP1 trapping [ 22 ].…”

Discovery of an NAD+ analogue with enhanced specificity for PARP1

“…In addition, the selectivity of ADO-3′-N3-NAD + for PARP1 over PARP2 may be attributed to structural differences in the vicinity of the substrate acceptor site. 43–47 In comparison to the acceptor pocket of PARP1, the one for PARP2 features a uniquely extended loop (Leu547-Thr553), possibly affecting substrate activity of ADO-3′-N3-NAD + for PARP2-catalyzed PARylation.…”

A Novel PARP Inhibitor YHP-836 For the Treatment of BRCA-Deficiency Cancers

“…Although clinical benefits of PARP inhibitors have been proved, safety issues such as hematological toxicity need to be addressed ( Farres et al, 2013 ; LaFargue et al, 2019 ). The next generation of PARP inhibitors is under development, targeting selective PARP1, to remedy the adverse events caused by inhibition of PARP2 ( Curtin and Szabo, 2020 ; Dias et al, 2021 ; Johannes et al, 2021 ; Ngoi et al, 2021 ). Secondly, the PK characteristics of YHP-836 did not support its further development.…”