Saruparib (AZD5305)

Saruparib (AZD5305) is a highly selective and potent inhibitor of PARP1 with an IC50 of 3 nM in wild-type A549 lung cancer cells. AZD5305 shows no or minimal growth inhibitory effects in other cells (IC50s >10μM).

AZD5305 is highly selective inhibitor for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species. AZD5305 reduces anti-proliferation effects on human bone marrow progenitor cells in vitro.

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DLD-1 and BRCA2^(-/-) DLD-1 cells are harvested to a density of 5000 cells/mL and 2.5 × 10⁴ cells/mL, respectively, in complete media, 40 μL/well seeded into 384-well plates using a Multidrop Combi then incubated at 37 °C, 5% CO2 overnight. The next day (day 1) using a Multidrop Combi, sytox green (5 μL, 2 μM) and saponin (10 μL, 0.25% stock) to a day 0 plate are added, the plate is sealed using a black adhesive lid and incubated for >3 h at rt. Cells are imaged using Cell Insight fitted with a 4× objective. AZD5305 is added using an Echo 555 and placed in an incubator maintained at 37 °C, 5% CO2 and incubated for 7 days. On day 8, sytox green (5 μL, 2 μM) and then saponin (10 μL, 0.25% stock) is added to plates, the plate is sealed using a black adhesive lid and incubated for >3 h at rt. All cells are read on a Cell Insight with 4× Objective. 

AZD5305 is a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model.^{<a class="sref" href="#s_ref">[2]</a>}