Design, Synthesis and Biological Evaluation of Small-Molecule Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is involved in the occurrence and development of the tumors, and is regarded as an attractive therapeutic target for cancer therapy. Our laboratory discovered some STAT3 inhibitors containing benzothiazole scaffold through virtual screening before. In a continuing effort to develop more potential STAT3 inhibitors, twenty-one target compounds based on our identified hit compound (16v) were rational designed and synthesized. These structures were characterized by H NMR, C NMR and HRMS. All the target compounds were tested for their inhibitory activity using a STAT3 luciferase reporter system. The results showed that many compounds displayed better activity than lead compound 16v in series I. However, compounds containing thiazolo[5,4-d]pyrimidine scaffold led to the loss of inhibitory activity. This may attributed to the losing of hydrogen bonding to Glu638.