Identification
of 6‑Anilino Imidazo[4,5‑c]pyridin-2-ones
as Selective DNA-Dependent Protein Kinase
Inhibitors and Their Application as Radiosensitizers
posted on 2024-07-15, 14:18authored byCho R. Hong, Lydia P. Liew, Way W. Wong, Benjamin D. Dickson, Gary Cheng, Avik Shome, Rebecca Airey, Jagdish Jaiswal, Barbara Lipert, Stephen M. F. Jamieson, William R. Wilson, Michael P. Hay
The dominant role
of non-homologous end-joining in the
repair of
radiation-induced double-strand breaks identifies DNA-dependent protein
kinase (DNA-PK) as an excellent target for the development of radiosensitizers.
We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure–activity studies
culminated in the identification of 78 as a nM DNA-PK
inhibitor with excellent selectivity for DNA-PK compared to related
phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families
and the broader kinome, and displayed DNA-PK-dependent radiosensitization
of HAP1 cells. Compound 78 demonstrated robust radiosensitization
of a broad range of cancer cells in vitro, displayed
high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C)
and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts
to radiation. Compound 78 also provided substantial tumor
growth inhibition of HCT116/54C tumor xenografts in combination with
radiation. Compound 78 represents a new, potent, and
selective class of DNA-PK inhibitors with significant potential as
radiosensitizers for cancer treatment.