A Small Molecule Compound Targeting STAT3 DNA-Binding Domain Inhibits Cancer Cell Proliferation, Migration, and Invasion

摘要

Signal transducer and activator oftranscription 3 (STAT3) playsimportant roles in multiple aspects of cancer aggressiveness includingmigration, invasion, survival, self-renewal, angiogenesis, and tumorcell immune evasion by regulating the expression of multiple downstreamtarget genes. STAT3 is constitutively activated in many malignanttumors and its activation is associated with high histological gradeand advanced cancer stages. Thus, inhibiting STAT3 promises an attractingstrategy for treatment of advanced and metastatic cancers. Herein,we identified a STAT3 inhibitor, inS3-54, by targeting the DNA-bindingdomain of STAT3 using an improved virtual screening strategy. InS3-54preferentially suppresses proliferation of cancer over non-cancercells and inhibits migration and invasion of malignant cells. Biochemicalanalyses show that inS3-54 selectively inhibits STAT3 binding to DNAwithout affecting the activation and dimerization of STAT3. Furthermore,inS3-54 inhibits expression of STAT3 downstream target genes and STAT3binding to chromatin in situ. Thus, inS3-54 represents a novel probefor development of specific inhibitors targeting the DNA-binding domainof STAT3 and a potential therapeutic for cancer treatments.