Alessio Sferrazza, Ilaria Rossetti, Danilo Fabbrini, Esther Torrente, Nicola Relitti, Federica Ferrigno, Paola Fezzardi, Costanza Iaccarino, Monica Bisbocci, Antonella Cellucci, Davide Ventre, Luca Anzillotti, Simone Palombo, Martina Nibbio, Cristina Alli, Christian Montalbetti, Carlo Toniatti, Alessia Petrocchi (2025). Bioorganic & Medicinal Chemistry Letters, Volume 129, 2025, 130383, ISSN 0960-894X, https://doi.org/10.1016/j.bmcl.2025.130383.
SHP2 as a Therapeutic Target
Src homology phosphotyrosine phosphatase 2 (SHP2), encoded by PTPN11, is a ubiquitously expressed non-receptor protein tyrosine phosphatase. It plays a central role in several signaling pathways, including RAS/MAPK, JAK/STAT, and PI3K/AKT, regulating cell proliferation, differentiation, migration, and metabolism. Aberrant SHP2 activation has been linked to oncogenesis and multiple diseases such as Noonan and LEOPARD syndromes, juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors including breast, lung, and colon cancers.
Given its pivotal role upstream of RAS in the RAS/RAF/MEK/ERK cascade, SHP2 is considered a high-value oncology target. While tool compounds such as SHP099 and the clinical candidate TNO155 have validated SHP2 as a druggable protein, there remains a strong need for new chemical matter with differentiated pharmacological properties.
Discovery of Azabicyclic SHP2 Inhibitors
As part of a broader drug discovery program, the research team identified an original series of allosteric SHP2 inhibitors featuring a novel azabicyclic primary amino group. Structure–activity relationship (SAR) studies around this moiety, combined with modifications of the heteroaryl portion of the molecule, produced highly potent inhibitors.
Key findings include:
- Potency and Activity: The compounds showed robust inhibition of SHP2 enzymatic activity and downstream pERK signaling, confirming effective MAPK pathway blockade.
- Cellular Efficacy: Selected inhibitors demonstrated antiproliferative activity in the KYSE-520 cancer cell line.
- Optimization: Extensive medicinal chemistry optimization improved physicochemical properties and reduced in vitro liabilities, including off-target hERG inhibition.
- Lead Candidate: Among the series, compound 21 emerged with excellent biochemical potency, cellular activity, and a suitable intravenous pharmacokinetic profile in rats, though oral exposure required further refinement.
Graphical Abstract
Implications for Drug Development
The discovery of SHP2 inhibitors with azabicyclic scaffolds highlights several important points for oncology drug discovery:
- Novel Chemical Space: The azabicyclic moiety represents a new structural feature in SHP2 inhibition, expanding the chemical diversity of drug candidates.
- Allosteric Modulation: Targeting the allosteric pocket allows selective SHP2 inhibition, reducing the risk of off-target phosphatase inhibition.
- With multiple SHP2 inhibitors in clinical trials but none yet approved, this new series provides additional opportunities for advancing SHP2-targeted therapies toward translational and preclinical studies.
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Additional references are available in the full article: https://doi.org/10.1016/j.bmcl.2025.130383