Discovery of Novel Heterotricyclic Compounds as DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Enhanced Chemosensitivity, Oral Bioavailability, and the Ability to Potentiate Cancer Immunotherapy

In this work, a novel series of heterotricyclic DNA-PK
inhibitors
were rationally designed, synthesized, and assessed for their biological
activity. In the DNA-PK biochemical assay, most compounds displayed
potent enzymatic activity, with IC50 values between 0.11
and 71.5 nM. Among them, SK10 exhibited the most potent
DNA-PK-inhibitory activity (IC50 = 0.11 nM). Studies of
the mechanism of action indicated that SK10 could lower
γH2A.X expression levels and demonstrate optimal synergistic
antiproliferative activity against Jurkat cells (IC50 =
25 nM) when combined with doxorubicin. Importantly, in CT26 and B16–F10
tumor-bearing mouse models, the combination therapies of SK10 with chemotherapeutic drug doxorubicin, a PD-L1 antibody, and SWS1 (a potent PD-L1 small-molecule inhibitor) demonstrated
superior synergistic anticancer and potential immunomodulatory effects.
Furthermore, SK10 possessed favorable in vivo pharmacokinetic
properties [e.g., oral bioavailability (F) = 31.8%].
Taken together, SK10 represents a novel heterotricyclic
DNA-PK inhibitor with antitumor immune effects and favorable pharmacokinetics.