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 Ki 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.

• Authors: Wei Huang, Yuan Liu, Jun Wang, Xia Yuan, Hong-Wei Jin, Liang-Ren Zhang, Jian-Ting Zhang, Zhen-Ming Liu, Jing-Rong Cui
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 157 Pg. 887-897 (Sep 05 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 30145375 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Hydrocarbons, Halogenated
• Ketones
• LC28 compound
• STAT3 Transcription Factor
• Small Molecule Libraries
• Cisplatin

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• DNA, Neoplasm (metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Hydrocarbons, Halogenated (chemical synthesis, chemistry, pharmacology)
• Ketones (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Protein Domains (drug effects)
• STAT3 Transcription Factor (antagonists & inhibitors, chemistry, metabolism)
• Small Molecule Libraries (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship