The blockade of immune checkpoint pathways is a key immunotherapeutic strategy. Several inhibitors, monoclonal antibodies, have been developed for the PD-1/PD-L1 pathway, a coinhibitory immune checkpoint pathway. However, due to acquired resistance, PD-1/PD-L1 monotherapy is not as efficient. Combination therapy with other class of inhibitors, for example DNA damage repair inhibitor (PARP inhibitors), have been shown to be more effective. Dual targeting drug conjugates share similarities with combination therapy, in the context of efficacy and potency. Additionally, drug conjugates are amenable to structural modification which may lead the enhancement of potency, and the improvement of pharmacokinetic properties of the conjugates.<br/>As the search for efficacious small molecule inhibitors of the PD-1/PD-L1 pathway continues, we report the first small molecule PARP-PD-L1 inhibitor conjugates. The design of these relatively efficacious inhibitors was informed by molecular modelling studies, and Chou-Talalay synergistic studies of olaparib, FDA approved PARP1 inhibitor and BMS-001, a small-molecule PD-L1 inhibitor.  The biological properties of these conjugates were assessed and compared to the individual inhibitors – olaparib and BMS001. These biological characterizations were accomplished via cell viability studies, FITC Annexin V/PI Apoptosis dead cell assay, cell cycle, cell-surface PD-L1 inhibition, immunoblotting, and T-cell proliferation assays. These conjugates were found to be comparatively superior, in terms of their ability to inhibit PARP1 protein, downregulate cell surface PD-L1 proteins. Also, these conjugates are relatively more cytotoxic - 2-20 times more potent.  Most importantly, our conjugates were metabolically stable. The conjugates also showed enhanced in vitro potency via late-stage apoptosis in triple negative breast cancer - MDA-MB-231.<br/>We contend that these conjugates can be used as a proof-of-concept tools to explore the crosstalk between PARP inhibition and PD-L1 pathway. These hybrid compounds also serve as good starting point for the design of a new class of potent, and efficacious small molecule PD-L1 inhibitors.

Small-molecule poly (ADP-ribose) polymerase (PARP) and PD-L1 inhibitor conjugates as dual-action anticancer agents

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.