# Diparlureas as Antitumor Agents
## 2 Diaylureas in Therapy or in Clinical Studies as Anticancer Agents  
### Sorafenib  
Sorafenib (BAY-43-9006, Nexavar(r), Figure 3) is an oral receptor TKI that determines the inhibition of Raf serine/threonine kinases and receptor tyrosine kinases (VEGF 1, 2, 3 and PDGF-\(\beta\), FMS-like tyrosine kinase-3 (FLT-3), and c-KIT) that are components of signaling pathways controlling tumor growth and angiogenesis [31]. Figure 2: Diaylureas in the type II kinase inhibitor. Sorafenib inhibits the kinase activity of C-RAF and B-RAF (wild type and V600E mutant) showing IC\({}_{50}\) = 6.22 and 38 nM, respectively. This compound is considered the most important drug in the late stage of injury for advanced stages of HCC [32] which is the second cause of cancer-related mortality all over the world [33]. For more than ten years, sorafenib has been the sole systemic treatment for advanced HCC [34]. However, some advanced HCC patients do not respond to therapy with sorafenib. Thus, combination studies of sorafenib with other drugs have been studied. Combined treatment with interferon-lambda 3 (IFN-3) and sorafenibb show an effect of synergism in suppressing HCC cancer growth and in the promotion of cell apoptosis in vitro and in vivo [35]. A more recent study demonstrated that combination immunotherapy of sorafenibb with aezolizumab, an immune checkpoint inhibitor (ICI) that target the programmed-cell death-1 receptor/ligand (PD-1/PD-L1) pathway, and bevacizumab, an anti-VEGF mAb, is superior to sorafenib alone as the first-line therapy of advanced HCC [36]. Moreover, given that liver function is essential for a correct prognosis, a precise rating for the safe prescription and clinical development of ICI in HCC is required. Recently, the albumin-bilirubin (ALBI) grade was used as an alternative biomarker for the prognosis [37]. The efficacy of sorafenibb is limited by several factors as systematic tolerance and the poor solubility in water. Furthermore, the hydrophobicity of sorafenibb is responsible of its low bioavailability as it decreases the absorption by the gastrointestinal tract. Nexavar(r) (Bayer Healthcare Pharmaceuticals-Onyx Pharmaceuticals) is used as tablets containing sorafenibb toylate to slightly improve the solubility. In order to increase the solubility and bioavailability of the drug, sorafenibb-loaded lipid-based nanosuspensions were used [38]. The administration of sorafenibb to the target cells could ameliorate patient survival and reduce the further proliferation of the tumor [39]. Thus, a drug delivery system for sorafenibb has been recently studied in order to help the administration of therapies in malignant cells and raise its clinical efficacy [40]. Recently, the treatment of cancers of the gastrointestinal tract during  
Figure 3: Structures of diarylureas. the COVID-19 pandemic [41] has been studied: coronavirus-adapted institutional recommendations have been formulated. Sorafenib was recommended in the first-line setting only in patients with disease subtype Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1 and Child-Pughscore A hepatocellular carcinoma [42]. In spite of its selectivity, sorafenib can determine adverse effects, such as severe respiratory and liver failure, fatigue, stomatitis, hand-foot syndrome, diarrhea, and myelosuppression, thus posing a challenge for oncologists [43]. The therapy with sorafenib might be done ad hoc to increase the therapeutic effects and reducing adverse effects [44]. Sorafenib is also studied for iodine-resistant advanced thyroid carcinoma [45]. Finally, it is important to note that sorafenib is also involved in cytoskeleton alteration that leads to cancer cells death by apoptosis. [PERSON] et al. [46] reported that the treatment of Hep3B and PLC/PRF/5 human hepatoma cells with sorafenib induces a drastic loss of actin fibers and the redistribution of F-actin around the cell nuclei.