Design, synthesis, and biological evaluation of novel azaspirooxindolinone derivatives as potent inhibitors of ITK and BTK-dependent cancers
Language English Country England, Great Britain Media print-electronic
Document type Journal Article
PubMed
40015119
DOI
10.1016/j.bmc.2025.118116
PII: S0968-0896(25)00057-4
Knihovny.cz E-resources
- Keywords
- Anti-cancer derivatives, Azaspirooxindolinones, Bruton’s tyrosine kinase, Interleukin-2-inducible T-cell kinase, Molecular docking,
- MeSH
- Protein Kinase Inhibitors * pharmacology chemical synthesis chemistry 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
- Antineoplastic Agents * pharmacology chemical synthesis chemistry MeSH
- Drug Design * MeSH
- Drug Screening Assays, Antitumor * MeSH
- Molecular Docking Simulation MeSH
- Spiro Compounds chemistry pharmacology chemical synthesis MeSH
- Protein-Tyrosine Kinases * antagonists & inhibitors metabolism 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
- emt protein-tyrosine kinase MeSH Browser
- Protein Kinase Inhibitors * MeSH
- Oxindoles MeSH
- Agammaglobulinaemia Tyrosine Kinase * MeSH
- Antineoplastic Agents * MeSH
- Spiro Compounds MeSH
- Protein-Tyrosine Kinases * MeSH
Interleukin-2-inducible T-cell kinase (ITK) and Bruton's tyrosine kinase (BTK) are two important members of the Tec family with crucial roles in immune system function. Deregulation in ITK and BTK activity is linked to several hematological malignancies, making them key targets for cancer immunotherapy. In this study, we synthesized a series of azaspirooxindolinone derivatives and evaluated their cytotoxic activity against ITK/BTK-negative and positive cancer cell lines, followed by enzymatic inhibition studies to assess the ITK/BTK kinase selectivity of two hit compounds. Several compounds demonstrated selective cytotoxicity against ITK- or BTK-expressing cells. Compound 3d exhibited high cytotoxicity in ITK-positive Jurkat (IC50 = 3.58 µM) and BTK-positive Ramos (IC50 = 3.06 µM) cells, while compound 3j showed strong cytotoxicity in Ramos (IC50 = 1.38 µM) and Jurkat (IC50 = 4.16 µM) cells. Compounds 3a and 3e were selectively cytotoxic in Jurkat cells (IC50 = 9.36 µM and 10.85 µM, respectively), while compounds 3f and 3g were highly cytotoxic in Ramos cells (IC50 = 1.82 µM and 1.42 µM, respectively). None of the active compounds exhibited cytotoxicity in non-cancer cell lines (IC50 > 50 µM), demonstrating their selectivity for malignant cells. Enzyme inhibition assay showed that 3d is a selective ITK inhibitor (IC50 = 0.91 µM) with no detectable BTK inhibition, aligning with its strong activity in ITK-positive cells. In contrast, compound 3j did not inhibit ITK or BTK enzymatically, suggesting an alternative mechanism of action. These findings highlight 3d as a promising ITK inhibitor and warrant further investigation to elucidate its mechanism of action.
Department of Chemistry School of Science GITAM University Hyderabad 502102 Telangana India
NATCO Research Center Sanath Nagar Industrial Area Sanath Nagar Hyderabad 500018 Telangana India
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