PARP1 选择性抑制剂和捕获剂 saruparib 在体外、体内及临床中实现延长的 PARP1 靶点结合

Saruparib (AZD5305) is a potent and selective inhibitor and trapper of PARP1 which is currently in ph3 clinical development. Initial preclinical characterisation highlighted nanomolar PARP1 inhibition potency and differentiated PARP1 binding profile with longer residence time kinetics compared with approved non-selective PARP inhibitors (PARPi). Here we describe the consequences of this in pre-clinical and clinical studies where we analysed PARP1 inhibition duration and phenotypic effects after different exposure times to saruparib. Surface plasmon resonance (SPR) of purified PARP1 showed that saruparib has a very slow dissociation rate, K off , and extended residence time on purified PARP1 protein (>5 days) compared to approved PARP1/2 inhibitors (hours). In cellular assays, saruparib treatment followed by wash-off resulted in sustained suppression of Poly ADP Ribose (PAR) over several days, whereas PAR levels recovered within 24 hours after olaparib exposure. We explored the duration of in vivo pharmacodynamic effects by monitoring PAR levels after steady state dosing of saruparib to mice bearing BRCA1-mutant MDA-MB-436 tumours, for up to 7 days after cessation of dosing. Saruparib at 0.01, 0.03 or 0.1mg/kg maintained PAR inhibition of >90% for up to 7 days, although the drug levels were not detectible in plasma after 2 days, confirming this extended duration of action in vivo . In contrast, PAR levels were substantially recovered by 24 hours after olaparib dosing. The functional consequences of the extended duration of action of saruparib were evaluated for in vivo efficacy. Multiple intermittent schedules of saruparib, compared to olaparib or talazoparib were evaluated in the BRCA1m-MDA-MB-436 model. Strong regressions were observed with saruparib on intermittent schedules where even 1 wk on, 2 wk off schedule at 1mg/kg (equivalent to the clinical RP2D dose of 60mg) gave durable regressions. A reduced dose of saruparib of 0.1mg/kg was still effective on an intermittent schedule, but lost significant activity compared to the higher dose. Intermittent dosing schedules of saruparib were clearly superior to the same schedules of olaparib or talazoparib at clinically equivalent doses. The long duration of activity of saruparib observed in preclinical studies were also observed in the PETRA clinical study (NCT04644068). A single dose of saruparib resulted in >90% PAR inhibition for up to 7 days, despite no drug being detected in plasma after 48 hours. These data suggest that short-term dose interruptions are unlikely to result in reduced efficacy, in contrast to approve non-selective PARPi where dose interruptions have been shown to reduce efficacy. These data also suggest that intermittent scheduling may be effective for saruparib in circumstances where minimising exposure may provide an optimal risk-benefit - for example cancer prevention.