Screening And Anti-cancer Activity Study Of Specific STAT3 Inhibitor

Lymphoma is one of the fastest-increasing cancers in the world.It is a systemic disease that is difficult to detect,rapid onset,and rapid death.More than 200,000 people died from lymphoma every year,which is showing a younger trend.Lymphoma has become a public health issue that cannot be ignored in our country and over the world.Signal transducer and activator of transcription 3(STAT3)protein often undergoes abnormal activation and mutation in lymphoma cells to promote their proliferation and anti-apoptosis ability.Thus,STAT3 has become an important target for the treatment of lymphoma.However,STAT3 is highly conserved in the STAT family,especially the SH2 domain is very similar to that of STAT1,which makes it difficult to obtain STAT3 inhibitor with high selectivity.So far,no inhibitors targeting STAT3 have been marketed.In recent years,natural product-like STAT3 inhibitors became attractive due to their novel structures,good anti-tumor activities,and high selectivity.These inhibitors hold great promise for further development.In this work,we designed a fluorescence polarization screening system for the discovery of specific STAT3 inhibitors.The natural product NR-1 and its analogs isolated from fungi in our laboratory were screened and identified with excellent binding affinity and selectivity to STAT3.NR-1 specifically targeted STAT3 protein,but not STAT1,thus inhibited the proliferation of lymphoma cells.In addition,NR-1 inhibited the activity of STAT3 hotspot mutations Y640F,A662V and N647I in lymphoma cells,and the D661 amino acid residue is an important site that affects the binding between NR-1 and STAT3.NR-1 also exhibited great in vivo efficacy in a nude mouse xenografted lymphoma cell model.It showed strong tumor inhibitory activities on both Karpass299-STAT3-WT and Karpass299-STAT3-Y640F cell xenograft tumors.In summary,our study has established a specific screening system for STAT3 inhibitors and identified natural product NR-1 as a specific STAT3 inhibitor with potent anti-tumor activity both in vitro and in vivo,which shed light on the development of natural product-like STAT3 inhibitors and provided a good starting point for STAT3 targeted therapeutics.