Identification of 6-Anilino Imidazo[4,5- c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers

  • J Med Chem. 2024 Jul 25;67(14):12366-12385. doi: 10.1021/acs.jmedchem.4c01120.
Cho R Hong  1 ,  Lydia P Liew  1 ,  Way W Wong  1 ,  Benjamin D Dickson  2 ,  Gary Cheng  1 ,  Avik Shome  1 ,  Rebecca Airey  1 ,  Jagdish Jaiswal  1 ,  Barbara Lipert  1 ,  Stephen M F Jamieson  1 ,  William R Wilson  1 ,  Michael P Hay  1
Affiliations
  • 1. Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • 2. Chemistry and Applied Physics, School of Science, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.
PMID: 39007759 DOI: 10.1021/acs.jmedchem.4c01120
Abstract

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.

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