New substituted quinoxalines inhibit triple-negative breast cancer by specifically downregulating the c-MYC transcription

Abstract

Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.

Alternative approaches to target Myc for cancer treatment

“…Besides, QN-1 potently downregulates MYC transcription in triple-negative breast cancer (TNBC) cells and effectively suppresses tumor growth in a TNBC mouse model. 22 One of the most cutting-edge researches related to small-molecule stabilizers of G-quadruplexes in handling Myc-deregulation is the Phase Ib study of APTO-253 in patients with relapsed or refractory acute myelogenous leukemia or high-risk myelodysplasia. 23 This inspiring clinical trial showed well-tolerated outcomes at the recommended dose in Phase 2 and evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors.…”

Scavenging of Labile Heme by Hemopexin Is a Key Checkpoint in Cancer Growth and Metastases

“…Therefore, G4s are considered to be ideal targets for anti-tumor drug development, and several ligands are being developed and tested for therapeutic approaches ( Balasubramanian et al, 2011 ; Biffi et al, 2014a ; Drygin et al, 2009 ; Guo and Bartel, 2016 ; Hänsel-Hertsch et al, 2016 ; McLuckie et al, 2013 ; Murat and Balasubramanian, 2014 ; Rodriguez et al, 2012 ). Notably, binding of small molecules and/or ligands to the G4 structures can activate an R-loop-dependent DNA damage response, which will ultimately lead to different cellular consequences commensurate with the concentration and chemical nature of the ligands as well as their binding mode and selectivity for specific G4 motifs ( Hampel et al, 2013 ; Hu et al, 2019 ; Paul et al, 2020 ; Amato et al, 2018 ).…”

Recent Developments in Small-Molecule Ligands of Medicinal Relevance for Harnessing the Anticancer Potential of G-Quadruplexes

“…The MYC proto-oncogene, first found to contain a possible G-quadruplex-formation site in the nuclease hypersensitive element III 1 (NHE III 1 ) of its promoter [75], has recently been targeted by a series of promising ligands (Figure 4). The quinoxaline QN1 has been demonstrated to efficiently suppress tumor growth in a triple-negative breast mouse model, believed to be a result of its selective action on MYC promoter [118]. Evidence provided, showed selective downregulation of MYC expression, while not affecting other G-quadruplex-forming proto-oncogene promoters, such as BCL2, KIT, VEGF and HRAS.…”

“…The quinoxaline QN1 has been demonstrated to efficiently suppress tumor growth in a triple-negative breast mouse model, believed to be a result of its selective action on MYC promoter [ 118 ]. Evidence provided, showed selective downregulation of MYC expression, while not affecting other G-quadruplex-forming proto-oncogene promoters, such as BCL2 , KIT , VEGF and HRAS .…”