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Discovery of novel and selective SIK2 inhibitors by the application of AlphaFold structures and generative models by Wei Zhu; Xiaosong Liu; Qi Li; Feng Gao; Tingting Liu; Xiaojing Chen; Man Zhang; Alex Aliper; Feng Ren; Xiao Ding; Alex Zhavoronkov is a Biochemistry, Genetics and Molecular Biology article available to read on EtoBox.

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Salt-inducible kinase 2 (SIK2) has been recognized as a potential target for anti-inflammation and anti-cancer therapy. In this paper, based on the binding pose of the reported compound (GLPG-3970, 3) with AlphaFold protein structure, a series of hinge cores were generated via AI-generative models (Chemistry42). After the molecular docking, synthesis, and biological evaluation, a hit molecule (7f) targeting SIK2 was obtained with a novel scaffold. Further SAR exploration led to the discovery of compound 8g with superior potency against SIK2 compared with the reported inhibitors. Furthermore, 8g also demonstrated excellent selectivity over other AMPK kinases, favorable in vitro ADMET profiles and decent cellular activities. This work provides an alternative approach to the discovery of novel and selective kinase inhibitors.

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Author

Wei Zhu; Xiaosong Liu; Qi Li; Feng Gao; Tingting Liu; Xiaojing Chen; Man Zhang; Alex Aliper; Feng Ren; Xiao Ding; Alex Zhavoronkov

Publisher

Elsevier BV

Published

2023

Language

EN

Field

Biochemistry, Genetics and Molecular Biology (Life Sciences)