Identification of a novel Azaspirooxindolinone-based PROTAC for selective BTK degradation and enhanced anticancer activity
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
40037026
DOI
10.1016/j.bioorg.2025.108316
PII: S0045-2068(25)00196-8
Knihovny.cz E-resources
- Keywords
- Antiproliferative activity, Azaspirooxindolinone, Bruton's tyrosine kinase, IL-2-inducible T-cell kinase, Jurkat, PROTAC, Ramos,
- MeSH
- Protein Kinase Inhibitors pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Oxindoles pharmacology chemistry chemical synthesis MeSH
- Cell Proliferation drug effects MeSH
- Agammaglobulinaemia Tyrosine Kinase * antagonists & inhibitors metabolism MeSH
- Proteolysis * drug effects MeSH
- Antineoplastic Agents * pharmacology chemistry chemical synthesis MeSH
- Drug Screening Assays, Antitumor MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- BTK protein, human MeSH Browser
- Protein Kinase Inhibitors MeSH
- Oxindoles MeSH
- Agammaglobulinaemia Tyrosine Kinase * MeSH
- Antineoplastic Agents * MeSH
Bruton's Tyrosine Kinase (BTK) is a key driver of hematological malignancies, autoimmune disorders, and neuroinflammation, making it an attractive therapeutic target. Proteolysis targeting chimeras (PROTACs) offer a novel strategy for BTK degradation via the E3 ubiquitin ligase pathway. Here, we evaluated nine azaspirooxindolinone-based PROTAC derivatives for their cytotoxicity and BTK-targeting activity. Several compounds exhibited potent cytotoxicity against BTK-high RAMOS lymphoma cells without affecting non-cancer fibroblasts or normal T/B-cell lymphocytes. Among them, PROTAC 25 emerged as the most effective degraded, achieving a Dmax of 72.84 % and DC50 of 0.27 μM in a proteasome-dependent manner. Although PROTAC 25 was cytotoxic to IL-2-inducible T cell Kinase (ITK)-positive cells, ITK protein levels remained unaffected. Furthermore, kinase assays revealed that PROTAC 25 inhibited BTK kinase activity (IC₅₀ = 0.44 μM) with moderate selectivity over ITK (IC₅₀ = 2.16 μM). Notably, PROTAC 25 suppressed BTK-mediated downstream signaling in RAMOS cells, as evidenced by reduced phosphorylation of BTK and its downstream effector, p38 MAPK. These findings highlight PROTAC 25 as a promising BTK degrader with therapeutic potential and underscore the value of azaspirooxindolinone-based PROTACs in targeting BTK-driven diseases.
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