Protein kinase B (AKT) (AKT)

Protein kinase B (AKT) is a serine/threonine-specific protein kinase that serves as a critical signaling node within the PI3K/AKT/mTOR pathway [StatPearls: Akt Signaling Pathway]. It regulates a wide array of cellular processes including cell proliferation, survival, growth, and glucose metabolism by phosphorylating diverse downstream substrates [UniProt: P31749]. In normal physiology, AKT is activated in response to growth factors and insulin through a multi-step process involving recruitment to the plasma membrane and phosphorylation by PDK1 and mTORC2 [NCBI: PMC6113119]. Hyperactivation of AKT is a hallmark of many human cancers, frequently driven by mutations in PIK3CA, AKT1, or the loss of the tumor suppressor PTEN [PubMed: 30045053]. This oncogenic signaling promotes chemotherapy resistance and uncontrolled tumor growth, positioning AKT as a high-priority target for drug development [FDA: Capivasertib approval]. Currently, several ATP-competitive and allosteric inhibitors are in clinical use or development, such as capivasertib, which was recently approved for specific breast cancer indications. However, the development of AKT inhibitors faces challenges due to the kinase's essential role in systemic glucose homeostasis, often leading to dose-limiting hyperglycemia. Efforts continue to refine the therapeutic window by identifying specific patient populations using biomarkers like AKT mutations or PTEN deficiency.

Other names

PKBAKT serine/threonine kinaseRAC-PK-alphaRAC-alpha serine/threonine-protein kinaseProtein kinase B alpha

ATP-competitive inhibition of AKT isoforms (1, 2, and 3) or allosteric inhibition preventing PH-domain mediated membrane translocation and subsequent activation.