Immune checkpoint blockades have revolutionized the treatment landscape for several cancer indications, yet they have not gained traction in a range of other tumors such as triple-negative breast cancer. Despite durable disease control by many patients, a third of cancer patients relapse due to acquired resistance. Combined immunotherapy has shown significant promise to overcome these grand challenges. In this report, we describe the synthesis and characterization of dual-action small-molecule PARP1/PD-L1 inhibitor conjugates as potential targeted anticancer agents. These conjugates display significant apoptosis and cytotoxic efficacy to approximately 2-20-fold better than their individual agents in a panel of cancer cell lines. This was underscored by derived combination indices, which was consistent with strong synergy when cells were treated with the individual agents, olaparib and BMS-001 using the Chou-Talalay method. Furthermore, we sought to unravel the mechanistic behavior of the conjugates and their implications on the PARP/PD-L1 axis. We used apoptosis, cell cycle, immunoblotting, and T-cell proliferation assays to establish the synergy imparted by these conjugates. These multifunctional compounds enable the discovery of small-molecule immunochemotherapeutic agents and chemical probes to elucidate the cross-talk between DNA repair and PD-L1 pathways.
|Number of pages||14|
|State||Published - Jul 24 2019|
Bibliographical noteFunding Information:
Financial support was provided by the University of Kentucky (UK). This study made use of the UK NMR facility, with funds from the MRI Program (grants CHE-0319176 and CHE-1625732) as well as UK Flow Cytometry & Immune Function core facility is supported in part by the Office of the Vice President for Research, the Markey Cancer Center, and an NCI Center Core Support Grant (P30 CA 177558) to the University of Kentucky Markey Cancer Center.
© 2019 American Chemical Society.
ASJC Scopus subject areas
- Chemistry (all)
- Chemical Engineering (all)