Definition

A heterobifunctional small molecule degrader of the protein signal transducer and activator of transcription 3 (STAT3) composed of a STAT3-binding moiety and a E3 ligase-binding moiety, with potential antineoplastic activity. Upon administration, the STAT3 degrader KT-333 specifically targets and binds to STAT3, thereby targeting STAT3 for degradation. Upon binding, endogenous E3 ubiquitin ligase is then recruited to STAT3 by the E3 ligase recognition moiety of KT-333, resulting in the tagging of STAT3 by ubiquitin. This causes ubiquitination and degradation of STAT3 by the proteasome, and prevents STAT3 activation, STAT3-mediated signaling and the expression of STAT3 target genes. This inhibits the proliferation of STAT3-overexpressing tumor cells. STAT3 regulates the transcription of genes involved in several cellular functions. STAT3 is constitutively activated in a variety of human cancers and plays a key role in neoplastic transformation, uncontrolled tumor cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial-mesenchymal transition (EMT) and the Warburg effect.