# Diparlureas as Antitumor Agents
###### Abstract  
The diarylurea is a scaffold of great importance in medicinal chemistry as it is present in numerous heterocyclic compounds with antithrombotic, antimalarial, antibacterial, and antiinflammatory properties. Some diarylurea, serine-threonine kinase or tyrosine kinase inhibitors, were recently reported in literature. The first to come into the market as an anticancer agent was sorafenibib, followed by some others. In this review, we survey progress over the past 10 years in the development of new diarylureas as anticancer agents.  
Keywords:diarylurea; antitumor agents; bis-aryl ureas; hepatocellular carcinoma (HCC); renal cell carcinoma (RCC); gastrointestinal stromal tumors (GISTs); metastatic colorectal cancer (mCRC); B-cell lymphomas +
Footnote †: journal: Medical  
xenograft models and were able to introduce cross-linking within the DNA double strand. Diarylurea-based compounds present strong inhibitory activity against kinases, including RAF kinases [12], platelet derived growth factor receptor (PDGF) [13], vascular endothelial growth factor receptor 2 (VEGFR-2) [14], receptor tyrosine kinase (RTKs) [15], and Aurora kinases [16]. The diarylurea moiety is, in fact, widespread in type II kinase inhibitors. These compounds circumvent kinases in an inactive state, the so-called DFG-out, and occupy a hydrophobic pocket next to the ATP-binding site. The diarylurea fragment is able to link the hinge-binding moiety with the portion that occupies the hydrophobic pocket that is in the inactive conformation of kinases [17] (Figure 2).  
Diaylureas represent the skeleton of the main systemic therapies for several cancers, as advanced, metastatic hepatocellular carcinoma (HCC) [18], advanced renal cell carcinoma (RCC) [19], gastrointestinal stromal tumors (GISTs) [20], metastatic colorectal cancer (mCRC) [21]. Sorafenib is a multi-targeted small molecule tyrosine protein kinase that improves median survival over placebo for unresectable HCC patients [22]. In 2008 it obtained Food and Drug Administration (FDA) and European Medicinal Agency (EMEA) approval for the treatment of RCC and HCC [23]. Basing on sorafenibb as the lead compound, several other diarylurea derivatives, such as regorafenib, linfanib, tivozanib, and ripretinib have been synthesized and evaluated as kinase inhibitors. Regorafenib was approved by the FDA in the United States in February 2013 in patients with advanced GISTs for those who had failed on imatinib and sunitinib [24; 25]. Linfanib is currently being studied in HCC clinical trials [26]. Unlike the other inhibitors of VEGFR and PDGFR, linfanib seems to be also involved in adipocyte browning, thus being considered for the treatment of obesity [27]. Tivozanib is a diarylurea which is to be considered as third and fourth line therapy in patients with metastatic RCC in phase 3 study [28]. By end of 2019, the Chinese and European regulatory authorities have marketed five small-molecule protein kinase inhibitors (PKIs), including tivozanib [29]. Ripretinib has been suggested as a promising treatment for advanced GISTs [30]. In this paper, these already known drugs bearing a diarylurea skeleton are reviewed, along with new synthetic diarylureas described in the literature as promising agents for the treatment of diverse type of tumors.