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| Item Type: | Article |
|---|---|
| Title: | Probing 3-amino-2H-azaindazoles as allosteric inhibitors of the protein tyrosine phosphatase SHP2 |
| Creators: |
Amoussa, Machoud, Efrém, Nina-Louisa, Li, Feng, Guo, Ziqiong, Roske, Yvette  ORCID: https://orcid.org/0000-0001-6237-388X, Frank, Katrin Jana, Pach, Szymon, Wolf, Clemens Alexander, Bo, Feng, Lesina, Marina, Kintzel, Mika, Alsalim, Rana, Zeitz, Victoria, Csorba, Noémi, Radetzki, Silke ORCID: https://orcid.org/0000-0003-2688-2868, Keserű, György M., Daumke, Oliver ORCID: https://orcid.org/0000-0002-6190-1414, Algül, Hana, Wolber, Gerhard, Li, Jia and Nazaré, Marc ORCID: https://orcid.org/0000-0002-1602-2330
|
| 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(WT) IC(50) = 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(50) 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. |
| Keywords: | 2H-Indazoles, Allosteric Inhibition, Heterocycles, Phosphatases, SHP2 |
| Source: | ChemMedChem |
| ISSN: | 1860-7179 |
| Publisher: | Wiley |
| Volume: | 21 |
| Number: | 11 |
| Page Range: | e70341 |
| Date: | 15 June 2026 |
| Official Publication: | https://doi.org/10.1002/cmdc.70341 |
| PubMed: | View item in PubMed |
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