AUTHOR=Bonilla Pedro Andrade , Hoop Cody L. , Stefanisko Karen , Tarasov Sergey G. , Sinha Sourav , Nicklaus Marc C. , Tarasova Nadya I. 

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1144153

DOI=10.3389/fonc.2023.1144153

ISSN=2234-943X

ABSTRACT=<p>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.</p>