Virtual screening of ultra-large chemical libraries identifies cell-permeable small-molecule inhibitors of a “non-druggable” target, STAT3 N-terminal domain

17 January 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


STAT3 N-terminal domain is a promising molecular target for cancer treatment and modulation of immune responses. However, STAT3 is localized in the cytoplasm, mitochondria, and nuclei, and thus, is inaccessible to therapeutic antibodies. Its N-terminal domain lacks deep pockets on the surface and represents a typical "non-druggable" protein. In order to successfully identify potent and selective inhibitors of the domain, we have used virtual screening of billion structure-sized virtual libraries of make-on-demand screening samples. The results suggest that the expansion of accessible chemical space by cutting-edge ultra-large virtual compound databases can lead to successful development of small molecule drugs for hard-to-target intracellular proteins.


Virtual screening
transcription factor
chemical space
virtual libraries
Microscale Thermophoresis


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