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.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

DNA-Activated Protein Kinase*/antagonists & inhibitors ; DNA-Activated Protein Kinase*/metabolism ; Biological Availability* ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/pharmacokinetics ; Antineoplastic Agents*/therapeutic use ; Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/pharmacokinetics ; Protein Kinase Inhibitors*/chemistry ; Protein Kinase Inhibitors*/therapeutic use; Humans ; Animals ; Mice ; Administration, Oral ; Immunotherapy/methods ; Doxorubicin/pharmacology ; Structure-Activity Relationship ; Cell Proliferation/drug effects ; Mice, Inbred BALB C ; Drug Discovery ; Mice, Inbred C57BL ; Cell Line, Tumor ; Drug Synergism ; Female

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 IC 50 values between 0.11 and 71.5 nM. Among them, SK10 exhibited the most potent DNA-PK-inhibitory activity (IC 50 = 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 (IC 50 = 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.

EC 2.7.11.1 (DNA-Activated Protein Kinase)
0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
80168379AG (Doxorubicin)

Date Created: 20240408 Date Completed: 20240425 Latest Revision: 20240425

20240425

10.1021/acs.jmedchem.3c02231

38587857