Priya, BhanuBhanuPriyaDubey, GuruduttGuruduttDubeyKirubakaran, SivapriyaSivapriyaKirubakaran2025-08-312025-08-312023-02-0710.1021/acsomega.2c073562-s2.0-85147312538http://repository.iitgn.ac.in/handle/IITG2025/26895Frequent mutation in the ATM/P53 signaling pathway has been documented in many human cancers. Reportedly, cancer cells with deficient P53/ATM pathways depend on functional Ataxia-telangiectasia and Rad3-related (ATR) protein for survival. This has prompted research in developing ATR inhibitors for the selective sensitization of cancer cells that are P53/ATM-deficient, but no clinical success has been attained thus far. This study explores the therapeutic potential of SPK98, an analogue of Torin2 in P53- and ATM-deficient cancer cells. Furthermore, the prospect of improving the therapeutic outcome of the genotoxic agent was also explored. SPK98 was shown to inhibit full-length human ATR protein purified from HEK293T cells. Cellular investigation using SPK98 demonstrated that it selectively sensitizes P53- and ATM-deficient cells at low concentrations compared to P53-/ATM-proficient cells. Furthermore, SPK98 drives the cancer cells toward cell death by promoting the formation of DNA double-strand breaks. Taken together, our findings suggest that SPK98 is a promising therapeutic molecule for P53- or ATM-deficient malignancy that merits additional preclinical investigation.trueArticlehttps://doi.org/10.1021/acsomega.2c07356247013434954-49627 February 20233arJournal4WOS:000926706400001