2. Academic Validation
  3. Novel azabicyclic series of potent SHP2 allosteric inhibitors

Novel azabicyclic series of potent SHP2 allosteric inhibitors

  • Bioorg Med Chem Lett. 2025 Dec 15:129:130383. doi: 10.1016/j.bmcl.2025.130383.
Alessio Sferrazza 1,  Ilaria Rossetti 2,  Danilo Fabbrini 2,  Esther Torrente 2,  Nicola Relitti 2,  Federica Ferrigno 2,  Paola Fezzardi 2,  Costanza Iaccarino 2,  Monica Bisbocci 3,  Antonella Cellucci 2,  Davide Ventre 2,  Luca Anzillotti 2,  Simone Palombo 2,  Martina Nibbio 2,  Cristina Alli 3,  Christian Montalbetti 2,  Carlo Toniatti 4,  Alessia Petrocchi 2
Affiliations

Affiliations

  • 1 Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy. Electronic address: a.sferrazza@irbm.com.
  • 2 Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.
  • 3 Department of Translational Biology, IRBM S.p.A., 00071 Pomezia, Rome, Italy.
  • 4 CSO - IRBM S.p.A., 00071 Pomezia, Rome, Italy.
PMID: 40840719 DOI: 10.1016/j.bmcl.2025.130383
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.

Keywords

Allosteric inhibition; Azabicyclo[4.1.0]heptane; Oncology; Phosphatase; SHP2; pERK.

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