mk-2206
Overview
MK-2206 is an allosteric pan-AKT inhibitor that binds the pleckstrin homology (PH) domain of AKT1, AKT2, and AKT3, locking the enzyme in an inactive conformation. Unlike ATP-competitive inhibitors (e.g., gsk-690693), its mechanism requires an intact PH domain on the target, limiting efficacy against AKT fusion proteins that lack this domain.
Evidence in the corpus
- MK-2206 failed to inhibit GSK3β phosphorylation driven by the MAGI3-AKT3 fusion kinase in breast cancer, because the fusion protein lacks the PH domain required for allosteric inhibitor binding PMID:22722202.
- In contrast, the ATP-competitive AKT inhibitor gsk-690693 was effective against the same fusion, establishing a mechanistic basis for inhibitor class selection in fusion-positive tumors PMID:22722202.
- In high-grade urothelial bladder carcinoma (n=97), PIK3CA-mutant and AKT1-mutant cell lines were selectively sensitive to MK-2206 while TSC1-null lines were resistant at the S6/4EBP1 level despite proximal AKT inhibition, mirroring KRAS-driven EGFR-therapy resistance PMID:23897969.
Resistance mechanisms
- Activating AKT fusions that delete or disrupt the PH domain (e.g., MAGI3-AKT3) are intrinsically resistant to PH-domain allosteric inhibitors including MK-2206 PMID:22722202.
Cancer types (linked)
- BRCA — triple-negative subtype with MAGI3-AKT3 fusions (PH-domain loss confers allosteric inhibitor resistance).
Sources
This page was processed by entity-page-writer on 2026-05-06. - PMID:23897969
This page was processed by wiki-cli on 2026-05-09.