Identification of a novel Azaspirooxindolinone-based PROTAC for selective BTK degradation and enhanced anticancer activity
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40037026
DOI
10.1016/j.bioorg.2025.108316
PII: S0045-2068(25)00196-8
Knihovny.cz E-zdroje
- Klíčová slova
- Antiproliferative activity, Azaspirooxindolinone, Bruton's tyrosine kinase, IL-2-inducible T-cell kinase, Jurkat, PROTAC, Ramos,
- MeSH
- inhibitory proteinkinas farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- oxindoly farmakologie chemie chemická syntéza MeSH
- proliferace buněk účinky léků MeSH
- proteinkinasa BTK * antagonisté a inhibitory metabolismus MeSH
- proteolýza * účinky léků MeSH
- protinádorové látky * farmakologie chemie chemická syntéza MeSH
- screeningové testy protinádorových léčiv MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- BTK protein, human MeSH Prohlížeč
- inhibitory proteinkinas MeSH
- oxindoly MeSH
- proteinkinasa BTK * MeSH
- protinádorové látky * 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.
Citace poskytuje Crossref.org
