Small-molecule compounds targeting the STAT3 DNA-binding domain suppress survival of cisplatin-resistant human ovarian cancer cells by inducing apoptosis

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) plays important roles in oncogenic occurrence and transformation by regulating the expression of diverse downstream target genes important for tumor growth, metastasis, angiogenesis and immune evasion. Feasibility of targeting the DNA-binding domain (DBD) of STAT3 has been proven previously. With the aid of 3D shape- and electrostatic-based drug design, we identified a new STAT3 inhibitor, LC28, and its five analogs, based on the pharmacophore of a known STAT3 DBD inhibitor. Microscale thermophoresis assay shows that these compounds inhibits STAT3 binding to DNA with a K value of 0.74-8.87 μM. Furthermore, LC28 and its analogs suppress survival of cisplatin-resistant ovarian cancer cells by inhibiting STAT3 signaling and inducing apoptosis. Therefore, these compounds may serve as candidate compounds for further modification and development as anticancer therapeutics targeting the DBD of human STAT3 for treatment of cisplatin-resistant ovarian cancer.

STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

“…LC28 is identified as a STAT3 DBD inhibitor through the pharmacophore of the inS3-45 analog A18. The compound inhibits the survival of cisplatin-resistant ovarian cancer cells [ 191 ]. An LC28 analog, MMPP exhibits the strongest binding affinity to STAT3 and binds selectively to the DBD, especially to T456.…”

A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment

“…This likely drives autocrine signaling. Interestingly, synergistic pathway cross-talk most likely exists between the STAT3 and PPARA as they converge on upregulation of nuclear expression of CPT1 [228,229] driving FAO as an energy source in breast cancer-adipose associations. While adiponectin signaling functionally inhibits CPT1 activity (Figure 3), and has been correlated with of inhibition of STAT3 signalling in cancer, the differential expression of adiponectin receptors in the presence of leptin may reduce this inhibition, allowing for STAT3 mediation of adipocytokine signalling and promotion of breast cancer phenotypes allowing adipose tissue to create a fostering niche for cancer to thrive [230][231][232].…”

Synthesis, Characterization, Photoluminescence, Molecular Docking and Bioactivity of Zinc (II) Compounds Based on Different Substituents

“…However, there are also serious side effects such as nephrotoxicity, neurotoxicity, gastrointestinal toxicity, bone marrow suppression and drug resistance [ 8 , 9 , 10 ], among others. These side effects limit the application of platinum drugs and promote the development of alternative therapeutics [ 11 , 12 , 13 ]. The production of novel anticarcinogen medicines, which are less toxic, are more effective and target specific but show high efficacy in chemotherapy, is an active area of research [ 14 , 15 ].…”