Discovery of Novel Heterotetracyclic DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Improved Oral Bioavailability and Potent Cancer Immunotherapy-Potentiating Activity

A novel
series of heterotetracyclic DNA-PK inhibitors
was rationally
designed, synthesized, and biologically evaluated. Most compounds
showed potent DNA-PK inhibition (IC50: 10.2–88.9
nM), with lead D11 (IC50 = 10.2 nM) inducing
γH2A.X upregulation and robust antiproliferative activity across
six cancer cell lines. Remarkably, D11 exhibited excellent
pharmacokinetics in SD rats (oral bioavailability: 42.6%; half-life:
50 h) and outperformed the clinical candidate AZD-7648 in LoVo xenografts (TGI = 72.9% vs 54.6% at 50 mg/kg, p.o.). It
also synergized with anti-PD-L1 mAb to enhance CD8+ T-cell
infiltration. Overall, D11 is a promising heterotetracyclic
DNA-PK inhibitor with superior in vivo efficacy,
favorable pharmacokinetics, and immunomodulatory potential, supporting
further development.