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| Home > Publications database > Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition. |
| Journal Article | DKFZ-2026-02213 |
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2026
Wiley-VCH
Weinheim
Abstract: The Akt family of serine/threonine kinases plays a crucial role in various cellular processes, including proliferation, survival, and metabolism. Three Akt isoforms (Akt1, Akt2, and Akt3) have distinct physiological roles, and while individual isoform dysregulation is disease-linked, unselective Akt inhibition leads to side effects. Here, we report the development of selective covalent-allosteric Akt inhibitors (CAAIs) targeting Akt2 and Akt3 while sparing Akt1. Guided by protein x-ray crystallography and molecular modeling, key structural differences within the allosteric pockets of the isoforms were identified and exploited in a structure-based design strategy. By stabilizing the inactive kinase conformation, CAAIs overcome the intrinsic selectivity limitations of ATP-competitive inhibitors. After biological characterization, the pyrazole-containing inhibitors emerged as the most potent and selective Akt2 inhibitors, while inhibitors with pyridines as an isoform-selective element were predominantly targeting Akt3 selectively. Importantly, these new inhibitors were also evaluated in patient-derived colorectal cancer organoids. Co-crystal structures of inhibitors bound to an engineered construct mimicking the Akt2 allosteric pocket elucidated the molecular basis of isoform selectivity, guiding further optimization. This work not only establishes a framework for the development of isoform-selective therapeutics but also highlights the potential for unraveling isoform-specific functions in signaling pathways relevant to cancer biology.
Keyword(s): Akt isoform‐selectivity ; allosteric modulation ; covalent inhibition ; structure‐based‐drug‐design
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