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Updated: Sep 10, 2025
Preparation of Stable Bicyclic Aziridinium Ions and Their Ring-Opening for the Synthesis of Azaheterocycles
Published on: August 22, 2018
Novel azabicyclic series of potent SHP2 allosteric inhibitors
Alessio Sferrazza1, Ilaria Rossetti1, Danilo Fabbrini1
1Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.
Abstract:
The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is a critical component of the RAS/RAF/MEK/ERK signaling pathway, functioning upstream of RAS to promote oncogenic signaling and tumor growth. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of original azabicyclic compounds was identified. Extensive preliminary SAR around the novel bicyclic basic moiety (left-hand side) and the heteroaryl portion (right-hand side) yielded a highly potent series of SHP2 inhibitors with demonstrated cellular potency (pERK inhibition, as downstream marker of MAPK pathway activity) as well as antiproliferative activity in a KYSE-520 cancer cell line. Further optimization of the physicochemical properties and reduction of in vitro off-target liabilities, including hERG inhibition, led to the identification of a unique series of SHP2 inhibitors with strong potential for development in efficacy studies using appropriate animal models.
Insights
Researchers developed novel allosteric SHP2 inhibitors to target cancer growth. These potent compounds show promise in cellular assays and may advance to animal studies for further efficacy evaluation.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- SHP2 phosphatase is crucial for RAS/RAF/MEK/ERK signaling, promoting oncogenic activity and tumor progression.
- Targeting SHP2 offers a therapeutic strategy for various cancers driven by aberrant MAPK pathway signaling.
Purpose of the Study:
- To discover and optimize novel allosteric inhibitors of SHP2.
- To identify compounds with potent cellular activity and favorable drug-like properties for cancer therapy.
Main Methods:
- Structure-activity relationship (SAR) studies were performed on a novel series of azabicyclic compounds.
- In vitro assays assessed SHP2 inhibition, pERK inhibition (MAPK pathway marker), and antiproliferative activity in KYSE-520 cancer cells.
- Physicochemical properties and off-target liabilities (e.g., hERG inhibition) were optimized.
Main Results:
- A potent series of allosteric SHP2 inhibitors based on an azabicyclic scaffold was identified.
- Compounds demonstrated significant cellular potency, including pERK inhibition and antiproliferative effects.
- Optimization led to improved physicochemical properties and reduced off-target liabilities.
Conclusions:
- Novel azabicyclic compounds effectively inhibit SHP2 and downstream signaling pathways.
- Optimized inhibitors exhibit potent anti-cancer activity in cellular models.
- These SHP2 inhibitors represent promising candidates for further preclinical development in animal models.
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