VEGFER-2 INHIBITORS AND QUINAZOLINE-BASED ANTICANCER AGENTS

Inhibitors of vascular endothelial growth factor receptor -2 (VEGFR-2) are crucial biological targets for the development of novel anticancer medications. Quinazoline also plays an important role as one of the building elements of numerous anticancer drugs. Thus, a review of the literature on VEGFR-2 inhibitors and Quinazoline-based anticancer medicines has been completed. We introduced VEGFR-2 inhibitors now undergoing clinical evaluation, such as Gefitinib, Erlotinib, Vandetanib, Afatinib, Lenvatinib, Cabozantinib, Sorafenib and Regorafenib in our survey. Additionally, VEGFR-2 inhibitors that are under development were introduced.


Introduction
Cancer is a major public health problem worldwide and is the second leading cause of death.In 2020, the diagnosis and treatment of cancer was hampered by the coronavirus disease 2019 (COVID-19) pandemic.For example, reduced access to care because of health care setting closures resulted in delays in diagnosis and treatment that may lead to a short-term drop in cancer incidence followed by an ultimately increased mortality (Rebecca et al. 2021).

Diseases of genes cause Cancer:
Inherited or somatic alterations in genes are what make a normal cell ignore growth-controlling signals and form a tumor that eventually leads to the destruction of the organism (Shipitsin et al. 2008).Possibly as many as 30% of cancers are caused by smoking, while another 30% are diet related.Carcinogenic chemicals in smoke, food and the environment may cause cancer by inducing gene mutations or interfering with normal cell differentiation.The birth of a cancer (carcinogenesis) can be initiated by a chemical-usually a mutagen but other triggering events, such as exposure to further mutagens, are usually required before a cancer develops (Patrick et al. 2013).

VEGF receptor
Vascular endothelial growth factor (VEGF) has been identified as the most common regulator of tumor angiogenesis, vascular permeability, endothelial cell activation, proliferation and migration (Ferrara et al. 2003).The VEGF family of genes contains at least 7 members, including the viral genome-derived VEGF-E, whereas the VEGFR family of genes has 3 to 4 members depending on the vertebrate species.VEGF-A and its receptors VEGFR-1 and VEGFR-2 play major roles in physiological as well as pathological angiogenesis, including tumor angiogenesis.VEGF-C/D and their receptor VEGFR-3 can regulate angiogenesis at early embryogenesis but mostly function as critical regulators of lymphangiogenesis (Shibuya et al. 2011).VEGFR-2 is over-expressed in several malignancies, including hepatocellular carcinoma, breast, colorectal, ovarian and thyroid cancer, melanoma and medulloblastoma (Otrock et al. 2007, Gershtein et al. 2010, Smith et al. 2010).

Gefitinib
Gefitinib (Iressa®) (1) was approved by the FDA in 2003 for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) (Brehmer et al. 2005).
Regarding the effectiveness of Gefitinib within NSCLC patients having an epidermal growth factor receptor (EGFR) mutated status, Gefitinib was found to have elevated efficacy levels in salvage and within NSCLC patients carrying the exon 19 deletion mutation and/or exon 21 Leu858Arg mutation status.(Kanagalingam et al. 2023)

Erlotinib
In 2004, Erlotinib (Tarceva®) (2) was approved by FDA for treating NSCLC.Furthermore, in 2005, FDA approved Erlotinib in combination with Gemcitabine for the treatment of locally advanced, unrespectable, or metastatic pancreatic cancer.Erlotinib acts as a reversible tyrosine kinase inhibitor (Shepherd et al. 2005).Although in 2023 , The results of this prospective phase II study will provide evidence on the safety and antitumor activity of combination therapy with Ramucirumab plus Erlotinib in patients with EGFR exon 19 deletion-positive treatment-naïve NSCLC with high PD-L1 expression (Kawachi et al. 2023).
In April 2011, Vandetanib became the first drug to be approved by the FDA for treatment of late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery (Commander et al. 2011).Genotyping is a predictor of response to Vandetanib and Cabozantinib since patients with an M918T mutation presented with a greater response to Vandetanib in comparison with M918T-negative patients (54.5% vs. 32%) (Martins et al. 2023)

Afatinib
Afatinib (Gilotrif®) (4) was approved by the FDA in 2013 for NSCLC treatment.It acts as an irreversible covalent inhibitor of the receptors tyrosine kinase (RTK) for EGFR and (HER2) (Ismail et al. 2016).The results support the notion that Afatinib has an overall advantage over first-generation EGFR-TKIs in the treatment of rare EGFR mutations and is adequate as a first-line treatment preference for NSCLC patients with major uncommon and compound mutation categories among rare EGFR mutations (Jiang et al. 2023)

Cabozantinib
Cabozantinib ( 5) is a multikinase inhibitor that targets VEGFR-2, MET, and RET-TS (Yakes et al. 2011).Cabozantinib was granted orphan-drug status by the FDA in 2012 for progressive metastatic medullary thyroid neoplasms (Norman et al. 2015).Cabozantinib is associated with a fast and significant volume reduction of brain radionecrosis appearing after SRS and concomitant immunotherapy (Lolli et al. 2023)

Sorafenib and Regorafenib
Sorafenib (7) (Nexavar ® ) is a biarylurea multitargeted kinase inhibitor.It inhibits VEGFR-2 and VEGFR-3 (Wilhelm et al. 2006).Sorafenib is an oral tyrosine kinase inhibitor with the ability to inhibit tumor cell proliferation and angiogenesis.It has been the first-line option for the group of patients with HCC since it received Food and Drug Administration (FDA) approval in 2008 (Zeng et al. 2023) In addition, Regorafenib (8) (Stivarga ® ), a fluoro derivative of Sorafenib developed by Bayer (Wilhelm et al. 2004), inhibits angiogenic kinases VEGFR-1/3.Furthermore, it showed anti-proliferative activities on different cancer cell lines (Wilhelm et al. 2011).It acts on various tyrosine kinase receptors, including oncogenic, stromal, and angiogenic receptors.Moreover, Regorafenib is highly indicated in the treatment of colorectal cancer, especially in metastatic form.It is also indicated for gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma (Baz et al. 2023) On September 27, 2012, the FDA approved Regorafenib (8) for the previously treated metastatic colorectal cancer (mCRC) and then in February 2013, FDA expanded the approved use of Regorafenib to treat patients with advanced gastrointestinal stromal tumors (GIST) (DiGiulio et al. 2013).

VEGFR inhibitors under development
Chandrika et al (Chandrika et al. 2008), synthesized a series of 2,4,6-trisubstituted quinazoline derivatives.By screening these derivatives for antiinflammatory and anticancer activities against U937 leukemia cell, it found that compound (9) was the most active one.
Kovalenko and co-workers (Kovalenko et al. 2013) The synthesized compounds were screened in vitro for their anti-proliferative activities.Compounds ( 13) and (14a-c) were the most active members.
Derivatives of 3-benzyl-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor activities (Al-Suwaidan et al. 2016).The results of this study indicated that compounds (18, 19 and 20) possess amazing broad spectrum antitumor activities with mean GI50 values nearly about 1.5 -3.0-fold more potent than that of positive control, 5-FU.
Zhao et al. designed and synthesized a class of 5-anilinoquinazoline-8-nitro derivatives that inhibit VEGFR-2 tyrosine kinase.The in-vitro cytotoxic activity assay and chick chorioallantois membrane assay showed that these compounds possess antitumor activity and anti-angiogenesis (Zhao et al. 2019).
Biological results showed that compounds 27a and 27b are of particular interest as anticancer agents targeting VEGFR-2 kinase in 2022 Abdallah et al.In addition to their considerable inhibition of VEGFR-2, they have shown promising antitumor effects especially against hepatocellular cancer cell line (HepG2) with high degree of selectively (Abdallah et al. 2022).
In 2023, Zari et al. examined the antiproliferative activities of some quinazoline derivatives against a panel of three human cancer cell lines (A549, SW-480, and MCF-7) using MTT assay.Among the tested compounds (29) showed the highest antiproliferative activities against the tested cell lines.This compound could also induce apoptosis in A549 cell line in a dose dependent manner (Zare et al. 2023).
The molecule (30) displayed a potent cytotoxic activity with IC50 = 5.4 nM against the VEGFR-2 kinase enzyme in 2023 by Zayed et al.It also showed 130% growth inhibition on the full NCI panel of cancer cell lines when exposed to in vitro antiproliferative assay (Zayed et al. 2023).

Figure 1 :
Figure 1: Statistics of cancer cases in Egypt (World Health Organization March,2021).