Cancer treatment by inhibiting the PD-1/PD-L1 pathway using
monoclonal antibodies has made great advances as it showed long-lasting antitumor responses in a wide range of
cancers. However,
antibodies exhibit several disadvantages, which include low permeability, immune-related adverse effects, complex synthetic procedures, and high treatment costs. Hence, small-molecule inhibitors can be used as alternatives; however, no small molecule with in vivo activity has been reported. In addition, there are many challenges in developing a new
drug, including the timeline and escalating cost. Therefore, repurposing an approved
drug offers advantages over the development of an entirely new
drug. Herein, we identify an FDA-approved small-molecule
drug,
Ponatinib, as a
PD-L1 inhibitor via virtual
drug screening of the
ZINC database.
Ponatinib showed stable binding with PD-L1, with the highest binding energy among all of the screened FDA-approved drugs. The binding of
Ponatinib with PD-L1 was supported by a fluorescence quenching assay and immunofluorescence study. Further, we compared the in vivo antitumor efficacy of
Ponatinib with a commercially available anti-PD-L1 antibody in the murine
melanoma model.
Ponatinib was found to be more efficient in delaying
tumor growth than the anti-PD-L1 antibody. Furthermore,
Ponatinib also reduced the expression of PD-L1 in
tumors and increased the T-cell population. Interestingly, splenocytes isolated from
Ponatinib-treated mice showed enhanced cytotoxic T-cell (CTL) activity against B16-F10 cells. However,
Ponatinib itself did not have any direct toxic effect on
cancer cells in vitro. These findings suggest that
Ponatinib can be used as a potent small-molecule inhibitor of PD-L1 to overcome the disadvantages associated with
antibodies.