Identification of a novel Azaspirooxindolinone-based PROTAC for selective BTK degradation and enhanced anticancer activity
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F25%3A73630464" target="_blank" >RIV/61989592:15640/25:73630464 - isvavai.cz</a>
Alternative codes found
RIV/00098892:_____/25:10159182 RIV/61989592:15110/25:73630464
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0045206825001968?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206825001968?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bioorg.2025.108316" target="_blank" >10.1016/j.bioorg.2025.108316</a>
Alternative languages
Result language
angličtina
Original language name
Identification of a novel Azaspirooxindolinone-based PROTAC for selective BTK degradation and enhanced anticancer activity
Original language description
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 mu M 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 mu M) with moderate selectivity over ITK (IC50 = 2.16 mu M). 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
BIOORGANIC CHEMISTRY
ISSN
0045-2068
e-ISSN
1090-2120
Volume of the periodical
157
Issue of the periodical within the volume
04/2025
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
108316
UT code for WoS article
001439775800001
EID of the result in the Scopus database
2-s2.0-85219022926