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

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

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.
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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