Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer.
Woong Sub ByunHyewon LimJunhwa HongEun Seo BaeSeok Beom LeeYounggwan KimJeeyeon LeeSang-Kook LeeSuckchang HongPublished in: Journal of medicinal chemistry (2023)
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.
Keyphrases
- cell cycle arrest
- induced apoptosis
- cell proliferation
- mouse model
- locally advanced
- cell death
- squamous cell carcinoma
- pi k akt
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- immune response
- radiation therapy
- transcription factor
- mass spectrometry
- risk assessment
- high resolution
- atomic force microscopy
- rectal cancer
- high speed
- nuclear factor