9TKU
Probing 3-Amino-2H-Azaindazoles as Allosteric Inhibitors of the Protein Tyrosine Phosphatase SHP2
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Summary for 9TKU
| Entry DOI | 10.2210/pdb9tku/pdb |
| Descriptor | Tyrosine-protein phosphatase non-receptor type 11, (1S)-1'-[3-azanyl-2-[2,3-bis(chloranyl)phenyl]pyrazolo[3,4-b]pyrazin-6-yl]spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine, ACETATE ION, ... (6 entities in total) |
| Functional Keywords | shp2 inhibition, 2h-indazoles, allosteric inhibitor, peptide binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 60989.53 |
| Authors | |
| Primary citation | Amoussa, M.,Efrem, N.L.,Li, F.,Guo, Z.,Roske, Y.,Frank, K.J.,Pach, S.,Wolf, C.A.,Bo, F.,Lesina, M.,Kintzel, M.,Alsalim, R.,Zeitz, V.,Csorba, N.,Radetzki, S.,Keseru, G.M.,Daumke, O.,Algul, H.,Wolber, G.,Li, J.,Nazare, M. Probing 3-Amino-2H-Azaindazoles as Allosteric Inhibitors of the Protein Tyrosine Phosphatase SHP2. Chemmedchem, 21:e70341-e70341, 2026 Cited by PubMed Abstract: Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is an attractive therapeutic target in oncology and immunology-related disorders. However, developing novel phosphatase inhibitors that combine high potency, selectivity, cellular permeability, and drug-like properties remains challenging. The discovery of an allosteric mode of inhibition for SHP2 was a breakthrough, enabling the development of selective inhibitors that stabilize the phosphatase in its inactive conformation. We identified 2H-indazoles as a privileged and underexplored scaffold. Using our recently described palladium-catalyzed domino reaction as a key synthetic step, 3-amino-2H-indazoles were efficiently accessed from readily available precursors, enabling rapid exploration of novel allosteric inhibitors of SHP2. This approach led to compound 17g, a potent and selective allosteric SHP2 inhibitor (SHP2 IC = 49 nM). High-resolution structural characterization by X-ray crystallography revealed binding within the SHP2 allosteric tunnel. Consistent with its biological activity, compound 17g also effectively suppressed ERK phosphorylation in MV-4-11, Panc-1, and KYSE520 cells with an IC of 50, 250, and 410 nM, respectively. These findings not only highlight the therapeutic potential of 2H-azaindazoles as a new class of SHP2 inhibitors but also underscore the importance of advances in efficient synthetic methodologies for constructing novel heterocyclic scaffolds and substitution patterns. PubMed: 42289381DOI: 10.1002/cmdc.70341 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.87 Å) |
Structure validation
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