Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth

Maresca, Luisa; Crivaro, Enrica; Migliorini, Francesca; Anichini, Giulia; Giammona, Alessandro; Pepe, Sara; Poggialini, Federica; Vagaggini, Chiara; Giannini, Giuseppe; Sestini, Serena; Borgognoni, Lorenzo; Lapucci, Andrea; Dreassi, Elena; Taddei, Maurizio; Manetti, Fabrizio; Petricci, Elena; Stecca, Barbara

doi:10.1016/j.phrs.2023.106858

Cited by 10 publications

(5 citation statements)

References 66 publications

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“…Thus QN-302 downregulates expression of the GLI1 gene encoding the major transcription factor GLI1 in the Hedgehog pathway to a greater extent than the other two compounds, which mostly affect expression of the GLI4 gene (Table 4 ). The GLI1 protein is significantly upregulated in human PDAC 45 – 47 and thus has been considered a potential therapeutic target 48 , since its up-regulation promotes migration and metastasis 46 . Genes for several other components of the Hedgehog pathway 49 are also downregulated by QN-302 (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that S100P 57 , 60 is a viable target in human cancers including PDAC, probably by inducing p53-related apoptosis 58 . The interaction of the GLI1 protein with selective quinoline-based small molecules 47 has been shown to down-regulate the Hedgehog signaling pathway by inhibiting GLI1-DNA binding and hence the transcription of GLI1 target proteins. This resulted in dose-dependent apoptosis in cancer cells, although the details of the mechanism involved have yet to be disclosed.…”

Section: Discussionmentioning

confidence: 99%

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Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Ahmed,

Chen,

Roman-Escorza

et al. 2024

Sci Rep

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The tetrasubstituted naphthalene diimide compound QN-302 binds to G-quadruplex (G4) DNA structures. It shows high potency in pancreatic ductal adenocarcinoma (PDAC) cells and inhibits the transcription of cancer-related genes in these cells and in PDAC animal models. It is currently in Phase 1a clinical evaluation as an anticancer drug. A study of structure–activity relationships of QN-302 and two related analogues (CM03 and SOP1247) is reported here. These have been probed using comparisons of transcriptional profiles from whole-genome RNA-seq analyses, together with molecular modelling and molecular dynamics simulations. Compounds CM03 and SOP1247 differ by the presence of a methoxy substituent in the latter: these two compounds have closely similar transcriptional profiles. Whereas QN-302 (with an additional benzyl-pyrrolidine group), although also showing down-regulatory effects in the same cancer-related pathways, has effects on distinct genes, for example in the hedgehog pathway. This distinctive pattern of genes affected by QN-302 is hypothesized to contribute to its superior potency compared to CM03 and SOP1247. Its enhanced ability to stabilize G4 structures has been attributed to its benzyl-pyrrolidine substituent fitting into and filling most of the space in a G4 groove compared to the hydrogen atom in CM03 or the methoxy group substituent in SOP1247.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Ahmed,

Chen,

Roman-Escorza

et al. 2024

Sci Rep

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“…In the case of sarcomas, it has been shown that GLI1 and GLI2 can be overexpressed in various types of sarcomas, both in bone (osteosarcomas) and soft tissue (rhabdomyosarcomas) [148][149][150].…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

“…Given all of the above, the possibility of inhibiting GLI1 and GLI2 may have beneficial effects in the treatment of all tumors with activation of these factors by suppressing the Hh activation pathway [147,150].…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

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Soft Tissue Sarcomas with Chromosomal Alterations in the 12q13-15 Region: Differential Diagnosis and Therapeutic Implications

Lavernia,

Claramunt,

Romero

et al. 2024

Cancers

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The chromosomal region 12q13-15 is rich in oncogenes and contains several genes involved in the pathogenesis of various mesenchymal neoplasms. Notable genes in this region include MDM2, CDK4, STAT6, DDIT3, and GLI1. Amplification of MDM2 and CDK4 genes can be detected in various mesenchymal and nonmesenchymal neoplasms. Therefore, gene amplification alone is not entirely specific for making a definitive diagnosis and requires the integration of clinical, radiological, morphological, and immunohistochemical findings. Neoplasms with GLI1 alterations may exhibit either GLI1 rearrangements or amplifications of this gene. Despite the diagnostic implications that the overlap of genetic alterations in neoplasms with changes in genes within the 12q13-15 region could create, the discovery of coamplifications of MDM2 with CDK4 and GLI1 offers new therapeutic targets in neoplasms with MDM2/CDK4 amplification. Lastly, it is worth noting that MDM2 or CDK4 amplification is not exclusive to mesenchymal neoplasms; this genetic alteration has also been observed in other epithelial neoplasms or melanomas. This suggests the potential use of MDM2 or CDK4 inhibitors in neoplasms where alterations in these genes do not aid the pathological diagnosis but may help identify potential therapeutic targets. In this review, we delve into the diagnosis and therapeutic implications of tumors with genetic alterations involving the chromosomal region 12q13-15, mainly MDM2, CDK4, and GLI1.

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Importin subunit beta‐1 mediates ERK5 nuclear translocation, and its inhibition synergizes with ERK5 kinase inhibitors in reducing cancer cell proliferation

Lombardi,

Gardini,

Kashchuk

et al. 2024

Molecular Oncology

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The mitogen‐activated protein kinase (MAPK) extracellular signal‐regulated kinase 5 (ERK5) is emerging as a promising target in cancer. Indeed, alterations of the MEK5/ERK5 pathway are present in many types of cancer, including melanoma. One of the key events in MAPK signalling is MAPK nuclear translocation and its subsequent regulation of gene expression. Likewise, the effects of ERK5 in supporting cancer cell proliferation have been linked to its nuclear localization. Despite many processes regulating ERK5 nuclear translocation having been determined, the nuclear transporters involved have not yet been identified. Here, we investigated the role of importin subunit alpha (α importin) and importin subunit beta‐1 (importin β1) in ERK5 nuclear shuttling to identify additional targets for cancer treatment. Either importin β1 knockdown or the α/β1 importin inhibitor ivermectin reduced the nuclear amount of overexpressed and endogenous ERK5 in HEK293T and A375 melanoma cells, respectively. These results were confirmed in single‐molecule microscopy in HeLa cells. Moreover, immunofluorescence analysis showed that ivermectin impairs epidermal growth factor (EGF)‐induced ERK5 nuclear shuttling in HeLa cells. Both co‐immunoprecipitation experiments and proximity ligation assay provided evidence that ERK5 and importin β1 interact and that this interaction is further induced by EGF administration and prevented by ivermectin treatment. The combination of ivermectin and the ERK5 inhibitor AX15836 synergistically reduced cell viability and colony formation ability in A375 and HeLa cells and was more effective than single treatments in preventing the growth of A375 and HeLa spheroids. The increased reduction of cell viability upon the same combination was also observed in patient‐derived metastatic melanoma cells. The combination of ivermectin and ERK5 inhibitors other than AX15836 provided similar effects on cell viability. The identification of importin β1 as the nuclear transporter of ERK5 may be exploited for additional ERK5‐inhibiting strategies for cancer therapy.

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Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth

Cited by 10 publications

References 66 publications

Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Structure–activity relationships for the G-quadruplex-targeting experimental drug QN-302 and two analogues probed with comparative transcriptome profiling and molecular modeling

Soft Tissue Sarcomas with Chromosomal Alterations in the 12q13-15 Region: Differential Diagnosis and Therapeutic Implications

Importin subunit beta‐1 mediates ERK5 nuclear translocation, and its inhibition synergizes with ERK5 kinase inhibitors in reducing cancer cell proliferation

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