Novel azabicyclic series of potent SHP2 allosteric inhibitors.
| Title: | Novel azabicyclic series of potent SHP2 allosteric inhibitors. |
|---|---|
| Authors: | Sferrazza A; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy. Electronic address: a.sferrazza@irbm.com.; Rossetti I; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Fabbrini D; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Torrente E; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Relitti N; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Ferrigno F; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Fezzardi P; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Iaccarino C; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Bisbocci M; Department of Translational Biology, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Cellucci A; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Ventre D; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Anzillotti L; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Palombo S; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Nibbio M; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Alli C; Department of Translational Biology, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Montalbetti C; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Toniatti C; CSO - IRBM S.p.A., 00071 Pomezia, Rome, Italy.; Petrocchi A; Department of Drug Discovery, IRBM S.p.A., 00071 Pomezia, Rome, Italy. |
| Source: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2025 Dec 15; Vol. 129, pp. 130383. Date of Electronic Publication: 2025 Aug 19. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Ltd; Original Publication: Oxford ; New York : Pergamon Press, c1991- |
| MeSH Terms: | Protein Tyrosine Phosphatase, Non-Receptor Type 11*/antagonists & inhibitors ; Protein Tyrosine Phosphatase, Non-Receptor Type 11*/metabolism ; Enzyme Inhibitors*/pharmacology ; Enzyme Inhibitors*/chemistry ; Enzyme Inhibitors*/chemical synthesis ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/chemistry ; Antineoplastic Agents*/chemical synthesis ; Aza Compounds*/chemistry ; Aza Compounds*/pharmacology ; Aza Compounds*/chemical synthesis; Allosteric Regulation/drug effects ; Cell Proliferation/drug effects ; Humans ; Structure-Activity Relationship ; Cell Line, Tumor ; Molecular Structure ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor |
| 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.; (Copyright © 2025 Elsevier Ltd. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Allosteric inhibition; Azabicyclo[4.1.0]heptane; Oncology; Phosphatase; SHP2; pERK |
| Substance Nomenclature: | EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); 0 (Enzyme Inhibitors); EC 3.1.3.48 (PTPN11 protein, human); 0 (Antineoplastic Agents); 0 (Aza Compounds) |
| Entry Date(s): | Date Created: 20250821 Date Completed: 20250922 Latest Revision: 20250922 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.bmcl.2025.130383 |
| PMID: | 40840719 |
| Database: | MEDLINE |
Journal Article