布鲁顿酪氨酸激酶
癌症研究
酪氨酸激酶
细胞毒性
淋巴瘤
药理学
细胞毒性T细胞
化学
免疫学
医学
生物化学
信号转导
体外
作者
Chandra Prakash Koraboina,Venkatanarayana Chowdary Maddipati,Narendran Annadurai,Soňa Gurská,Petr Džubák,Marián Hajdúch,Viswanath Das,Rambabu Gundla
标识
DOI:10.26434/chemrxiv-2023-19xm7
摘要
As a regulator of the dual function of apoptosis in B cells, Bruton's tyrosine kinase (BTK) was the first discovered tyrosine kinase. It continues to draw interest as a potential therapy for autoimmune disorders, inflammation, and malignancies connected to B cells. The pathogenic alterations in various cancer tissues depend on mutant BTK for cell proliferation and survival, and BTK is also overexpressed in a range of hematopoietic cells. Due to this, BTK is emerging as a potential drug target to treat various human diseases, and several reversible and irreversible inhibitors have been developed and are being developed. As a result, BTK inhibition, clinically validated as an anticancer treatment, is finding great interest in B-cell malignancies and solid tumours. This study focuses on the design and synthesis of new oxindole sulfonamide derivatives as promising inhibitors of BTK with negligible off-target effects. The most cytotoxic compounds with greater basicity were PID-4 (2.29 ± 0.52 µM), PID-6 (9.37 ± 2.47 µM), and PID-19 (2.64 ± 0.88 µM). These compounds caused a selective inhibition of Burkitt's lymphoma RAMOS cells without significant cytotoxicity in non-BTK cancerous and non-cancerous cell lines. Further, PID-4 showed promising activity in inhibiting BTK and downstream signalling cascades. As a potent inhibitor of Burkitt's lymphoma cells, PID-4 is a promising lead for developing novel chemotherapeutics.
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