Epidermal Growth Factor Receptor (EGFR) inhibitors for tumor anti-angiogenesis activity.

: The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation through effects on cell proliferation, differentiation, apoptosis, invasion, and angiogenesis. Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling, allowing them to proliferate under adverse conditions, invade surrounding tissues, and increase angiogenesis. Epidermal growth factor receptor (EGFR) is a trans-membrane receptor tyrosine kinase that belongs to the Human epidermal receptor (HER) family of receptors. Receptor protein tyrosine kinases play a key role in signal transduction pathways that regulate cell division and differentiation. Among the growth factor receptor kinases that have been identified as being important in cancer is epidermal growth factor receptor (EGFR) kinase (also known as erb-B1 or HER-1) and the related human epidermal growth factor receptor HER-2 (also known as erbB-2). The quinazoline and other heterocyclic skeletons are of great importance to chemists as well as biologists as it is available in a large variety of naturally occurring compounds. In this article we are emphasizing on various heterocycles such as Quinazoline, pyrrolotriazines etc. as promising anticancer agents. These heterocycles showed the anticancer activity through the inhibition of EGFR enzyme. Attempt will be taken to provide details information on the said topic in the benefit of medicinal chemist.


Introduction
The quinazoline 1 and other heterocyclic skeletons are of great importance to chemists as well as biologists as it is available in a large variety of naturally occurring compounds.It is also found in clinically useful molecules having diverse biological activities 2 such as antiviral 3, antimalarial 4 , Anticonvulsant 5,6 Antimicrobial 7,8 , Antitoxoplasmosis 9 , Antihyperglycemic 10, Antiplatelet 11 , Anxiolytic 12 , Antifungal 13 , Antihypertensive 14 .
Cancer chemotherapy has entered a new era of molecularly targeted therapeutics, which is highly selective and not associated with the serious toxicities of conventional cytotoxic drugs 15 .
The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation through effects on cell proliferation, differentiation, apoptosis, invasion, and angiogenesis 16,17 .Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways (Figure1), tumor cells often have dysregulated EGFR signaling, allowing them to proliferate under adverse conditions, invade surrounding tissues, and increase angiogenesis.Normally EGFR must be activated by a ligand to initiate downstream signaling, but tumor cells can circumvent this requirement through a number of mechanisms 18 .Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that belongs to the Human epidermal receptor (HER) family of receptors 19 .
The first group of these novel anticancer drugs is those targeting mutant or aberrantly expressed oncogenic growth factor receptor and non-receptor tyrosine kinases involved in mitogenic or proliferative signal transduction pathways in cancer cells. 20Receptor protein tyrosine kinases play a key role in signal transduction pathways that regulate cell division and differentiation.Among the growth factor receptor kinases that have been identified as being important in cancer is epidermal growth factor receptor (EGFR) kinase (also known as erb-B1 or HER-1) and the related human epidermal growth factor receptor HER-2 (also known as erbB-2).Deregulation of growth-factor signaling due to hyperactivation of the ErbB receptors (primarily EGFR and HER-2) is seen in several cancer types. 21,22Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand.In contrast, activation of HER-2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligand-independent manner. 23,24 ure1: EGFR pathway This review is originated from the literature survey on the quinazoline and other important heterocyclic moiety [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] which shows the good EGFR/VEGFR inhibitory activity.
Quinazoline is the chemical entity that shows a very good promising anticancer activity through the EGFR inhibition, some moieties which are developed for good EGFR inhibitor activity are as follows.4) and the quinazoline (5) and are reported to be ATP competitive inhibitors of VEGFR-2 and they confirmed their activities against this target.The compound 6 (IC 50 (nM) 1µM ATP=18.7)showed modest EGFR kinase inhibitory activity.Anilinoalkynyl pyrimidines were prepared and evaluated by Alex G. Waterson et al as dual EGFR/ErbB2 kinase inhibitors.A preference was found for substituted phenyl and heteroaromatic rings attached to the alkyne (15).In addition, the presence of a potential hydrogen bond donor appended to this ring was favored.

Harold
Mastalerz et al designed 14 compounds of Pyrrolotriazine dual EGFR/HER2kinase inhibitors in that a 5-((4-aminopiperidin-1-yl) methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups having IC 50 value 0.035.25 pyrrolotriazine dual EGFR and HER2 kinase inhibitors

Figure 2 Figure 3 27 R=OHFigure 4
Figure 2 Predicted binding mode of compound 1 modeled in the X-ray structure

6 Figure 5
Figure 5 Proposed binding model for 6 bound to the kinase domain of EGFR.

Figure 6 Figure 6 Guozhang
Figure 6 Binding model for 6 bound to the kinase domain of VEGFR-2.

Figure 8
Figure 8 Interactions between EGFR and compound 11.Compound 11 is shown

Caterina
Carmi et al synthesized series of 1,5-disubstituted hydantoins (14) some 1-phenethyl and a 5-(E)-benzylidene substituent, inhibits EGFR autophosphorylation and polyGAT phosphorylation, and also inhibits the growth and proliferation of human A431 cells, which overexpress EGFR.These compounds can therefore be regarded as examples of a new scaffold for tyrosine kinase inhibitors

34
new 6-alkoxy-4-substituted-aminoquinazolines (16-17) and their bioisoteric quinoline congeners were designed and synthesized by Khaled Abouzid et al.Most of the tested compounds exploited potent antitumor activity with IC 50 values in the nanomolar range.35The benzamides 18 and the benzamidines(19-20) were synthesized by Toru Asano et al as the mimics of 4-anilinoquinazolines, which possess inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase (IC 50 values are 0.09-0.32mM.)and tested for cytotoxicity toward A431 and inhibitory activity toward autophosphorylation by the enzyme assay.364-anilinoquinazolines 21 with C-C multiple bond substitutions at the 6-position were synthesized and investigated for their potential to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity by Hyun Seung Ban et al.These compounds inhibited EGF-mediated phosphorylation of EGFR in A431 cells, resulting in cell-cycle arrest and apoptosis induction.The C-C multiple bonds substituted at the C-6 position of the anilinoquinazoline framework were essential for the significant inhibitory activity.Compounds with long carbon chains (n = 3-6) shows prolonged inhibitory activity. 37Hubbard et al. developed 2-OMe substituted pyrazolopyrimidines 22 multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases.