1 research outputs found
Novel 5‑Substituted Oxindole Derivatives as Bruton’s Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation
Bruton’s tyrosine kinase (BTK) is a non-RTK cytoplasmic
kinase predominantly expressed by hemopoietic lineages, particularly
B-cells. A new oxindole-based focused library was designed to identify
potent compounds targeting the BTK protein as anticancer agents. This
study used rational approaches like structure-based pharmacophore
modeling, docking, and ADME properties to select compounds. Molecular
dynamics simulations carried out at 20 ns supported the stability
of compound 9g within the binding pocket. All the compounds
were synthesized and subjected to biological screening on two BTK-expressing
cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines,
A549, HCT116 (parental and p53–/–), U2OS,
JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and
MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h,
possessing free binding energies of −10.8, −11.1, −11.3,
and −10.8 kcal/mol, respectively, and displaying selective
cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated
the antiproliferative activity of 9h in RAMOS cells through
selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk,
upstream proteins in the BCR signaling pathway. In conclusion, we
identified a promising oxindole derivative (9h) that
shows specificity in modulating BTK signaling pathways