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 βcarboline 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.

Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures

“…Recently, aberrant activation of STAT3 has been considered to be correlated with acquired drug resistance. , Interestingly, HCT116-5-FU cells also exhibited hyperactivation of STAT3 compared to their parent HCT116 cells. However, lenziamide A treatment for 24 h effectively suppressed p-STAT3 expression in HCT116-5-FU cells, indicating the possibility of overcoming acquired anticancer drug resistance in CRCs (Figure c).…”

Potential therapeutic targets of the JAK2/STAT3 signaling pathway in triple-negative breast cancer

“…In vitro studies have demonstrated Napabucasin’s capability to reduce TNBC cell viability ( 156 ). Additionally, a series of compounds, such as 7a ( 157 ), SLSI-1216 ( 158 ), H182 ( 159 ), SMY002 ( 160 ), MC0704 ( 161 ), ZSW ( 162 ), and Acetyl-cinobufagin ( 163 ), have been identified to selectively inhibit STAT3 phosphorylation by binding to its SH2 domain and suppressing TNBC cell viability in vitro . Arctigenin, a bioactive lignan isolated from the seeds of Arctium lappa, inhibits STAT3 in TNBC cells by binding to its SH2 domain, thereby disrupting hydrogen bond connections between DNA and STAT3.…”

Current Status of Indole-Derived Marine Natural Products: Synthetic Approaches and Therapeutic Applications

“…Marinacarbolines A–D ( 263 – 266 ), obtained from Marinactinospora thermotolerant , and their synthetical derivatives, bear an additional C3-amido moiety with pendant aryl rings ( Figure 54 ). Their cytotoxicity was first investigated in 2015 [ 190 ] , but Hong and Lee have performed a very recent and in-depth SAR study against ocetaxel-Resistant Triple-Negative Breast Cancer [ 191 ]. Compounds 263 – 266 also exhibit promising antimalarial activity [ 129 ].…”

“…Penerpenes A-B (190,191) are two indole diterpenoids obtained from Penicillium sp. KFD28, isolated from a bivalve mollusk.…”