Design and Synthesis of Arf1-Targeting γ-Dipeptides as Potential Agents against Head and Neck Squamous Cell Carcinoma

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer-related deaths and calls for new druggable targets. We have previously highlighted the critical role of ADP-ribosylation factor-1 (Arf1) activation in HNSCC. In the present study, we address the question whether targeting Arf1 could be proposed as a valuable strategy against HNSCC. Methods: We rationally designed and synthesized constrained ATC-based (4-amino-(methyl)-1,3-thiazole-5-carboxylic acid) γ-dipeptides to block Arf1 activation. We evaluated the effects of these γ-dipeptides in HNSCC cells: The cell viability was determined in 2D and 3D cell cultures after 72 h treatment and Arf1 protein levels and activity were assessed by GGA3 pull-down and Western blotting assays. Results: Targeting Arf1 offers a valuable strategy to counter HNSCC. Our new Arf1-targeting compounds revealed a strong in vitro cytotoxicity against HNSCC cells, through inhibiting Arf1 activation and its downstream pathways. Conclusions: Arf1-targeting γ-dipeptides developed in this study may represent a promising targeted therapeutic to improve managing the HNSCC disease.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…ARF1 has been associated with resistance to anticancer drugs in various cancers [ 281 , 282 , 283 , 284 , 285 ]. ARF1 is a member among 29 human ARF family members that belong to the small GTPase RAS superfamily [ 286 , 287 ].…”

GTPase Pathways in Health and Diseases

“…Following our efforts to interfere with Arf1-GDP/Sec7-Arno, we explored the ability of constrained heteroaromatic γ-dipeptide scaffolds, so called 4-amino-(methyl)-1,3-thiazole-5-carboxylic acids (ATCs), to outline the key interacting elements of the Arno autoinhibitory domain. We rationally designed and synthesized constrained ATC-based γ-dipeptides to block Arf1 activation and examined their efficacy in head and neck squamous cell carcinoma [ 5 ]. Based on the observations in our previous study [ 6 ], we suggest that Arf1-targeting γ-dipeptides could be used in monotherapy or in combination with anti-EGFR agents for head and neck cancer treatment.…”

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“…Interestingly, a missense mutation of ARF1 (p.L148P), identified in a metastatic GIST tumor, was further verified in a relapsed GIST tumor of the test cohort, suggesting its potential role in GIST progression and therapeutic resistance. Several papers have reported that ARF1 could promote tumor development and metastasis in other cancer types, including breast cancer (Haines et al, 2014), cervical cancer (Xu and Zhang, 2020), prostate cancer (Davis et al, 2016), head and neck squamous cell carcinoma (Vo-Hoang et al, 2020). The pathologic role of this mutation is unclear and deserves for further investigations.…”