Identification of 1-pyrazolo[3,4-b]pyridine derivatives as novel and potent TBK1 inhibitors: design, synthesis, biological evaluation, and molecular docking study.

sABSTRACTTANK-binding kinase 1 (TBK1), a noncanonical member of the inhibitor-kappaB kinases (IKKs) family, plays a vital role in coordinating the signalling pathways of innate immunity, involving in the process of neuroinflammation, autophagy, and oncogenesis. In current study, based on rational drug design strategy, we discovered a series of 1-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure-activity relationships (SARs). Through the several rounds of optimisation, compound stood out as a potent inhibitor on TBK1 with an IC value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor as lead compound for immune- and cancer-related drug discovery.