Given the limitations of the existing antibody-based
therapies, including immune-related adverse events, poor response rates, and intravenous route of dosing, small molecules inhibitors targeting PD-L1 are highly desirable. By cell-based screening, we found that
tyrosine kinase inhibitor Bafetinib dramatically suppresses
PD-L1 protein expression in a dose-dependent manner. In parallel, cell membrane PD-L1 is also reduced by
Bafetinib. We confirm that
Bafetinib doesn't affect the
protein half-life of PD-L1 but significantly inhibits the transcription of PD-L1. Among the
transcription factors that regulate PD-L1 expression, c-Myc is downregulated by
Bafetinib.
Bafetinib caused PD-L1 inhibition is abolished when c-Myc is knocked-down. Further, we identified that
Bafetinib reduced c-Myc expression because of transcription inhibition. By using the CT26
tumor model, we further confirm that
Bafetinib suppressed PD-L1 expression in vivo. In conclusion, our study shows that
Bafetinib inhibits the transcription of PD-L1 through
transcription factor c-Myc, suggesting that
Bafetinib might be a small molecule drug targeting PD-L1.