Small-Molecule Poly(ADP-ribose) Polymerase and PD-L1 Inhibitor Conjugates as Dual-Action
Anticancer Agents
Posted on 2019-07-24 - 08:14
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.
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Ofori, Samuel; Awuah, Samuel G. (2019). Small-Molecule Poly(ADP-ribose) Polymerase and PD-L1 Inhibitor Conjugates as Dual-Action
Anticancer Agents. ACS Publications. Collection. https://doi.org/10.1021/acsomega.9b01106