Phosphatidylinositol 3-kinase-related kinase (PIKK) (PIKK)

The Phosphatidylinositol 3-kinase-related kinase (PIKK) family comprises six large serine/threonine kinases: ATM, ATR, DNA-PKcs, mTOR, SMG1, and TRRAP (Lovejoy & Cortez, 2009, J Cell Sci). Although they share sequence homology with the catalytic domain of phosphoinositide 3-kinases (PI3Ks), PIKKs are primarily protein kinases that regulate critical cellular processes including the DNA damage response (DDR), nutrient sensing, and mRNA decay (Blackford & Jackson, 2017, Mol Cell). ATM, ATR, and DNA-PKcs are central to maintaining genomic stability, acting as sensors that trigger cell cycle arrest and DNA repair in response to double-strand breaks and replication stress (UniProt). mTOR serves as a master regulator of cellular metabolism and growth, integrating signals from growth factors and nutrient availability (PubMed). In oncology, PIKKs are significant therapeutic targets; mTOR inhibitors like everolimus are FDA-approved, while inhibitors of ATR (e.g., berzosertib) and DNA-PK (e.g., peposertib) are being evaluated to enhance the efficacy of radiotherapy and chemotherapy (ClinicalTrials.gov). Therapeutic challenges include managing off-target toxicities such as myelosuppression and metabolic disturbances, as well as identifying predictive biomarkers like ATM deficiency for synthetic lethality approaches (Nature Reviews Drug Discovery).

Other names

PI3K-related kinasePIK-related kinasePhosphoinositide 3-kinase-related kinase

Inhibition of the catalytic kinase domain to disrupt signaling pathways involved in DNA repair, cell growth, or mRNA stability.