Hay, Michael PHong, Cho RLiew, Lydia PDickson, Benjamin DWong, Way WO'Brien-Gortner, Sophia FAirey, RebeccaJaiswal, JagdishWilson, William RJamieson, Stephen M2024-10-022024-10-022024-01-09(2024). Cancer Research, 84(1_Supplement), A001.0008-5472https://hdl.handle.net/2292/70128Inhibition of the repair of radiation-induced DNA double strand breaks (DSB) offers the potential to sensitize tumors to radiation therapy. The dominant role of non-homologous end-joining in the repair of radiation-induced DSBs indicates that DNA-dependent protein kinase (DNA-PK) is an excellent target for the development of radiosensitizers. We report the discovery of a new chemical class of kinase inhibitor based on the imidazo[4,5-c]pyridin-2-one scaffold. The class was developed by scaffold-hopping from the pan phosphoinositide 3-kinsase (PI3K) and PI3K-like kinase (PIKK) inhibitor dactolisib. Iterative development culminated in the identification of SN39536 as a low nM DNA-PK inhibitor with excellent selectivity. Further modification led to the discovery of the more potent and more selective SN40905. Both SN39536 and SN40905 were effective inhibitors of DNA-PK kinase activity in a biochemical assay with substantial selectivity for DNA-PK across the PIKK and PI3K families. Both compounds selectively inhibited growth of HAP1 PRKDC wild-type cells when combined with radiation, but not the corresponding PRKDC-/- cells. SN39536 and SN40905 were effective radiosensitizers of colorectal carcinoma (HCT116), non-small cell lung cancer (H460, H1299, and A549), pancreatic (BxPC-3, PANC-1, and MiaPaCa-2) and head and neck squamous cell carcinoma (FaDu and UT-SCC-74B) cells determined using a clonogenic survival endpoint. Both SN39536 and SN40905 displayed high oral bioavailability. When administered PO at a range of non-toxic doses, both SN39536 and SN40905 provided significant additional tumor cell killing of HCT116, UT-SCC-74B, and BxPC-3 tumor xenografts in combination with a single (13 Gy) radiation treatment determined by ex vivo clonogenic survival assays. SN39536 also provided substantial tumor growth inhibition of HCT116 tumor xenografts in combination with RAD (10 Gy). SN39536 and SN40905 represent a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for the treatment of human cancers.Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmhttps://creativecommons.org/licenses/by-nc-nd/4.0/32 Biomedical and Clinical Sciences3211 Oncology and CarcinogenesisCancerGeneticsLung CancerDigestive DiseasesLungRare DiseasesOrphan Drug5.1 Pharmaceuticals1112 Oncology and Carcinogenesis3101 Biochemistry and cell biologyConference Item10.1158/1538-7445.dnarepair24-a0012024-09-01Copyright: American Association for Cancer Researchhttp://purl.org/eprint/accessRights/OpenAccess1538-7445