Discovery of a fluorinated squaramide as a potential CXCR2- autophagy signalling modulator in chemo-resistant oral squamous cell carcinoma and polyploid giant cancer cells.

Oral squamous cell carcinoma (OSCC), a highly metastatic oral cancer subtype is associated with a poor prognosis, chemoresistance and low survival rate. Failed clinical outcomes by conventional chemotherapeutic drugs have proposed chemokine receptor inhibitors as novel chemotherapeutic agents. CXCR2, a key pro-inflammation regulator supporting cell proliferation, metastasis, and chemoresistance, is overexpressed in OSCC. Autophagy plays a dual role during cancer progression. At the late stage of OSCC, autophagy facilitates cell survival and chemoresistance. Under chemotherapeutic stress, polyploidization of tumour cells leads to the formation of polyploid giant cancer cells (PGCCs) that help in tumour relapses and metastasis. The present work is focused on the rational design and development of a fluorinated squaramide-based CXCR2 inhibitor as a chemotherapeutic agent against OSCC. Cell-free IL-8 receptor binding assay and computational analysis, along with cell-based protein expression analysis, projected compound 5 as a potent CXCR2 inhibitor. Mechanistically, compound 5 mediated CXCR2-Ca2+ signalling inhibition halted autophagic flux; subsequently facilitating ROS-mediated apoptotic cell death. In addition, compound 5 downregulated the CXCR2-NLRP3 canonical inflammation signalling. Moreover, compound 5 primed CAL27 cells exhibited enhanced chemosensitization towards cisplatin. Furthermore, compound 5 induced autophagy-dependent cell death in drug-resistant OSCC-derived PGCCs. Preliminary in vivo pharmacokinetic studies have also marked its safety for further pre-clinical application, indicating compound 5 as the hit CXCR2 inhibitor against OSCC. The outcomes of our investigation revealed the synthesis and screening of a potent fluorinated squaramide-based CXCR2 inhibitor as a robust next-generation chemotherapeutic agent for personalized and precision oncology with an insight into OSCC treatment.