9TMY
Akt1 mutant in complex with the 1-ethyl 1,5-substituted pyrazole containing compound
This is a non-PDB format compatible entry.
Summary for 9TMY
| Entry DOI | 10.2210/pdb9tmy/pdb |
| Descriptor | RAC-alpha serine/threonine-protein kinase, ~{N}-[3-[1-[[4-[5-[(2-ethylpyrazol-3-yl)methyl]-3-phenyl-pyridin-2-yl]phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide (3 entities in total) |
| Functional Keywords | akt1, akt2, akt3, covalent-allosteric, covalent inhibition, akt isoform selectivity, allosteric modulation, structure-based-drug-design, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 52313.77 |
| Authors | |
| Primary citation | D'Angelo, G.D.,Pervanidis, K.A.,Athanasiadis, I.,Lukianchikov, V.,Scrima, A.,Depta, L.,Stier, S.,Muller, M.P.,Farin, H.F.,Quambusch, L.,Rauh, D. Isoform-Selective Targeting of Akt Through Covalent Allosteric Inhibition. Angew.Chem.Int.Ed.Engl., :e3567206-e3567206, 2026 Cited by PubMed 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. PubMed: 42704227DOI: 10.1002/anie.3567206 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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