Covalent allosteric inhibitors exploit pocket differences to hit Akt2 or Akt3 while sparing Akt1, tested in organoids
- Structural and modeling work exposed isoform differences in Akt allosteric pockets, enabling covalent inhibitors that favor Akt2 or Akt3 over Akt1.
- Holding the kinase inactive sidesteps ATP-site selectivity limits; pyrazole compounds favored Akt2, pyridine ones mostly Akt3.
- Colorectal cancer organoids and co-crystal structures supported the selectivity rationale.
💡 Points Based on the abstract
The pocket differences between Akt isoforms are tiny, so I'd want to know how much of the Akt2/Akt3 discrimination comes from residue contacts and how much from warhead reactivity; ATP-site compounds never managed it. The pyrazole-for-Akt2, pyridine-for-Akt3 split is a usable SAR handle. Proteome-wide reactivity profiling comes before I believe any of it.
Isoform‐Selective Targeting of Akt Through Covalent Allosteric Inhibition ↗