Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer.

Abstract

Metastatic triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based on marinacarboline (MC), a series β-carboline derivatives were synthesized and investigated for their antitumor activities against docetaxel-resistant MDA-MB-231 (MDA-MB-231-DTR) cells. Combining antiproliferation and STAT3 inhibitory activities, MC0704 was selected as the most promising β-carboline compound. MC0704 effectively impeded the metastatic potential of MDA-MB-231-DTR cells in vitro, and the combination of MC0704 and docetaxel exhibited potent antitumor activities in a xenograft mouse model. These findings suggested that MC0704 can be a lead candidate as a target therapeutic agent for TNBC patients with docetaxel resistance.

• Authors: Woong Sub Byun, Hyewon Lim, Junhwa Hong, Eun Seo Bae, Seok Beom Lee, Younggwan Kim, Jeeyeon Lee, Sang Kook Lee, Suckchang Hong
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 4 Pg. 3106-3133 (02 23 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 36786551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Docetaxel
• STAT3 Transcription Factor
• Antineoplastic Agents
• STAT3 protein, human

Topics

• Humans
• Animals
• Mice
• Docetaxel (therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy)
• STAT3 Transcription Factor (metabolism)
• Apoptosis
• Xenograft Model Antitumor Assays
• Cell Line, Tumor
• Cell Proliferation
• Antineoplastic Agents (pharmacology)