Angira, DeekshiDeekshiAngiraShaik, AlthafAlthafShaikThiruvenkatam, VijayVijayThiruvenkatam2025-08-312025-08-312020-03-0110.2741/48672-s2.0-85080840644http://repository.iitgn.ac.in/handle/IITG2025/2420132114444Phosphatidylinositol-3 kinase-related kinases (PIKKs) is a class of six unique serine/threonine kinases that are characterized as high molecular mass colossal proteins present in multicellular organisms. They predominantly regulate the innumerable eukaryotic cellular processes, for instance, cell-signaling cascades related to DNA damage and repair, cell growth and proliferation, cell cycle arrest, genome surveillance, gene expression and many other important yet diverse functions. A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain. In this comprehensive review, we reassess and discuss various established functions of all the six PIKK members with each function corroborated by their structural topology. In addition to the domain architecture of these atypical kinases, their specific inhibitors have been briefly deliberated. This review gives us the impression of the emergent importance of PIKKs, which, despite of their complexity, are the hub of research with respect to the inhibitor development.trueAtaxia telangiectasia mutated kinase | ATM | ATM- and Rad3-related kinase | ATR | DNA damage response | DNA dependent protein catalytic subunit | DNA-PKcs | HSMG1 | Mammalian target of rapamycin | MTOR | Phosphatidylinositol-3 kinase-related kinases | PIKK | Suppressor with morphological effect on genitalia family member | Transformation-transactivation domain-associated protein | TRRAPArticle276866981538-15671 March 20209reJournal9WOS:000563770100006