HNC0014, a Multi-Targeted Small-Molecule, Inhibits Head and Neck Squamous Cell Carcinoma by Suppressing c-Met/STAT3/CD44/PD-L1 Oncoimmune Signature and Eliciting Antitumor Immune Responses

Abstract

Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exosp- and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development.

In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1

“…Hence, the identification of novel small molecules, which can regulate the overexpression of these genes, becomes crucial. We have earlier reported NSC777201 for some biological activities [ 25 , 26 , 67 ], herein, we used a molecular docking approach and an NCI’s ovarian cancer cell lines to evaluate its anti-cancer activity and explore its possibility for targeting TTK, NEK2, and CDK1. Interestingly, we found that NSC777201 exhibited anti-proliferative and dose-dependent cytotoxic activity against the NCI’s ovarian cancer cell lines.…”

“…The removal of water molecules, the addition of hydrogen atoms, and Kolmman charges in the receptor were made as prerequisites of pre-docking. Molecular docking studies were conducted using AutoDock VINA software and by following protocols described in our previous studies [ 67 , 83 , 84 , 85 ]. The best poses of ligand-receptor complexes of hydrogen bonds and electrostatic and hydrophobic interactions were expressed as binding energy values (kcal/mol) to represent docking results.…”

Pharmacoinformatics and Preclinical Studies of NSC765690 and NSC765599, Potential STAT3/CDK2/4/6 Inhibitors with Antitumor Activities against NCI60 Human Tumor Cell Lines

“…Pre-docking preparation of the receptors followed the removal of water molecules, while hydrogen atoms and Kolmman charges were added accordingly. Molecular docking studies were performed using Autodock VINA software and by following the protocols described in our previous study [3]. The docking results based on hydrogen bonds and electrostatic and hydrophobic interactions of the best pose of the ligand-receptor complexes were expressed as binding energy values (kcal/mol).…”

“…Despite advances in biomedical research, cancer remains a public health concern and is currently ranked the second leading cause of global mortality [1,2]. The etiology of cancer is often multifactorial, involving an interplay between genetic and epigenetic factors which amount to dysregulation of molecular networks, proteins, RNA, and DNA in favor of cell growth and proliferation [3,4]. The survival, growth, and metastasis of tumor cells depend on cellular differentiation, proliferation, angiogenic, and apoptotic mechanisms [5], which are controlled by a range of protein kinases and signal transduction pathways [6,7].…”

Computational and Preclinical Evidence of Anti‐ischemic Properties of L‐Carnitine‐Rich Supplement via Stimulation of Anti‐inflammatory and Antioxidant Events in Testicular Torsed Rats

“…The ligands were prepared for docking by deletion of H 2 O molecules, adjustment of polar hydrogen, and addition of Kollman charges. The molecular docking was performed using AutoDock Vina with all parameters set as default, and all bonds in the ligand are rotated freely, considering the receptor as rigid [57][58][59]. A grid box of 40 Å × 40 Å × 40 Å was generated on defined binding site residues of the ligand.…”