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

sABSTRACT

TANK-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 1H-pyrazolo[3,4-b]pyridine derivatives as potent TBK1 inhibitors and dissected the structure–activity relationships (SARs). Through the several rounds of optimisation, compound 15y stood out as a potent inhibitor on TBK1 with an IC₅₀ value of 0.2 nM and also displayed good selectivity. The mRNA detection of TBK1 downstream genes showed that compound 15y effectively inhibited TBK1 downstream IFN signalling in stimulated THP-1 and RAW264.7 cells. Meanwhile, compound 15y exhibited a micromolar antiproliferation effect on A172, U87MG, A375, A2058, and Panc0504 cell lines. Together, current results provided a promising TBK1 inhibitor 15y as lead compound for immune- and cancer-related drug discovery.

Keywords:

• TBK1 inhibitors
• 1H-pyrazolo[3,4-b]pyridine
• structure–activity relationships (SARs)
• immune response
• cancer therapy

Acknowledgements

We gratefully acknowledge the Program for Innovative Research Team of the Ministry of Education and the Program for Liaoning Innovative Research Team in University.

Disclosure statement

The authors declare no competing financial interest.

Additional information

Funding

We are grateful for financial support from the Lingang Laboratory Grant (LG202103-02–01 and LG202103-02–02) and the National Natural Science Foundation of China [Grant 82173658 and 81773572].