gsk-690693

Overview

GSK-690693 is an ATP-competitive pan-AKT inhibitor that blocks the kinase domain of AKT1, AKT2, and AKT3. Unlike allosteric inhibitors (e.g., mk-2206) that target the pleckstrin homology (PH) domain, GSK-690693 binds the ATP-binding site of the AKT catalytic domain, making it effective against activating fusions that lack an intact PH domain.

Evidence in the corpus

  • GSK-690693 inhibited constitutive GSK3β phosphorylation driven by the MAGI3-AKT3 fusion kinase in breast cancer, whereas the allosteric AKT inhibitor mk-2206 did not, because the fusion lacks the PH domain required for allosteric inhibitor binding PMID:22722202.
  • Findings suggest that triple-negative breast cancer patients with MAGI3-AKT3 fusions (found in ~6.9% of triple-negative cases) should be treated with ATP-competitive rather than allosteric AKT inhibitors PMID:22722202.

Resistance mechanisms

  • Allosteric AKT inhibitors (PH-domain targeting) such as mk-2206 are predicted to be ineffective against AKT3 fusion proteins that lack an intact PH domain PMID:22722202.

Cancer types (linked)

  • BRCA — triple-negative subtype with MAGI3-AKT3 fusions.

Sources

This page was processed by entity-page-writer on 2026-05-06.