Receptor tyrosine kinases (RTKs) are part of the larger family of protein tyrosine kinases. They are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Approximately 20 different RTK classes have been identified.[1]
Lapatinib is a EGFR inhibitor used in breast cancer treatment. ERBB2 is necessary for heart cells proliferation and regeneration[2].
Epidermal Growth Factor Receptors are overexpressed in many types of human carcinomas including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic Ras signalling cascade, resulting in uncontrolled DNA synthesis and cell proliferation. Studies have revealed that the is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.[3][4] Erlotinib inhibits the EGFR tyrosine kinase by located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.[5][6]
Gefitinib inhibits the EGFR tyrosine kinase by located within the kinase domain. Residues Lys 745, Leu 788, Ala 743, Thr 790, Gln 791, Met 193, Pro 794, Gly 796, Asp 800, Ser 719, Glu 762, & Met 766 tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.[7]
Erlotinib inhibits the EGFR tyrosine kinase by located within the kinase domain. EGFR uses residues Asp 831, Lys 721, Thr 766, Leu 820, Gly 772, Phe 771, Leu 694, Pro 770, Met 769, Leu 768, Gln 767 & Ala 719 to tightly bind the inhibitor. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.[8][9]
A Possible Strategy against Head and Neck Cancer: In Silico. Investigation of Three-in-One inhibitors[10]
(colored in darkmagenta), which is an enzyme with decarboxylation reaction of uroporphyrinogen III to (colored in salmon), is overexpressed in tumor tissues and has potential to sensitize cancer patients to radiotherapy. Moreover, (colored in magenta) and (colored in deeppink), which are tyrosine kinase receptors in the erbB family, are also overexpressed in tumor tissues and have been indicated as the important targets of therapy for cancer. In this research, we discuss the possible conformation for an inhibitor against three target proteins, UROD, EGFR, and Her2.
Virtual screening of the UROD (PDB ID: 1r3y), EGFR (PDB ID: 3poz), and Her2 (PDB ID: 3pp0) was conducted using the binding site defined by the volume and location of the co-crystallized compounds in each crystal structure. In silico results indicate the traditional Chinese medicine (TCM) compounds had high binding affinity with all three target protein. For (colored in magenta), the top three compounds, (colored in yellow), (colored in cyan), and (colored in orange), formed hydrogen bonds with the residues, Arg803, Lys913 and some other residues in the binding domain. The docking poses of (colored in deeppink) with (colored in yellow), (colored in cyan), and (colored in orange), exhibited hydrogen bonds between ligands and the residues in the binding site. For protein (colored in darkmagenta), (colored in yellow), (colored in cyan), and (colored in orange), have hydrogen bonds with the three important binding and catalytic residues Arg37, Arg41, Tyr164, and the residue His220. The three TCM compounds hint towards a probable molecule backbone which might be used to evolve drug-like compounds against EGFR, Her2, and UROD, and have potential application against head and neck cancer.
See also Herceptin - Mechanism of Action
Vascular Endothelial Growth Factor Receptors (VEGFRs) are tyrosine kinase receptors responsible for binding with VEGF to initiate signal cascades that stimulate angiogenesis among other effects[11]. VEGFRs convey signals to other signal transduction effectors via autophosphorylation of specific residues in its structure. Because VEGFRs are up-regulated in cancerous tumors which have a high metabolic need for oxygen, VEGFRs are an important target for pharmaceutical drugs treating cancer. VEGFR subtypes are numbered 1,2,3. The VEGFRs are a family of tyrosine kinase receptors on the surface of different cells depending on family identity. VEGFR-1 is expressed on haematopoietic stem cells, monocytes, and vascular endothelial cells. VEGFR-2 is expressed on vascular endothelial cells and lymphatic endothelial cells, while VEGFR-3 is only expressed on lymphatic endothelial cells[12]. The structure of VEGFR-2 can been seen at the right. VEGF-A binds to the second and third extracellular Ig-like domains of VEGFR-2 with a 10-fold lower affinity than it does to the second Ig-like domain of VEGFR-1, despite the fact that VEGFR-2 is the principal mediator of several physiological effects on endothelial cells including proliferation, migration, and survival.[13] Binding of VEGF to the domains 2 and 3 of a VEGFR-2 monomer increases the probability that an additional VEGFR-2 binds the tethered ligand to form a dimmer. Once the two receptors are cross-linked, interactions between their membrane-proximal domain 7s stabilize the dimmer significantly. This dimerization and stabilization allows for precise positioning of the intracellular kinase domains, resulting in autophosphorylation and subsequent activation of the classical extracellular signal-regulated kinases (ERK) pathway.[14].
The tyrosine kinase domain of VEGFR-2 is separated into two segments with a 70 amino acid long kinase insert region. Upon binding VEGFA and subsequent dimerization, VEGFR-2 is autophosphoryalted at the carboxy terminal tail and kinase insert region. Six tyrosine residues of VEGFR2 are autophosphorylated (see Fig.1[15]). within the activation loop of VEGFR2 leads to increased kinase activity[16]. (PDB code 3c7q).
Sorafenib inhibits cellular signaling by targeting several different receptor tyrosine kinases (RTKs) including receptors for platelet-derived growth factor (PDGFRs) and vascular endothelial growth factor receptors (VEGFR). PDGFR and VEGFR play crucial roles in both tumor angiogenesis and cellular proliferation. Sorafenib binds the ATP binding site of PDGFR & VEGFR, peventing the receptor kinase from binding ATP and phosphorylating their respective tyrosine target residues. Inhibition of PDGFR and VEGFR results in reduced tumor vascularization and cancer cell death. Sorafenib is also an inhibitor of KIT, a cytokine receptor inhibitor. Mutations of the KIT gene, often resulting in overexpression, are associated with cancerous tumors.[17] The KIT protein is at equilibrium between two predominant confirmations, the active conformation and the autoinhibited inactive conformation. In its active conformation, KIT binds to stem cell factors, upon which KIT dimerizes and transmits second messenger signals ultimately resulting in cell survival and proliferation. In its inactive conformation, the "DFG Triad" of KIT, residues Asp 810, Phe 811, Gly 812, is in the "out" position, with Phe 811 occupying the ATP binding site, preventing phosphorylation and signaling. The , is a good model for KIT as it shares numerous structural homologies, including conformations. Sorafenib inhibits p38 in an identical manner as it does KIT, by preferentially binding and stabilizing the autoinhibited inactive conformation of p38. using residues Glu 71, Leu 74, Val 83, Ile 166, His 148, Ile 84, Leu 167, Thr 106, His 107, Met 109, locking the inhibitor in place and stabilizing the receptor in the inactive state.[18]
Sunitinib inhibits cellular signaling by targeting several different receptor tyrosine kinases (RTKs) including receptors for platelet-derived growth factor (PDGFRs) and vascular endothelial growth factor receptors (VEGFR). PDGFR and VEGFR play crucial roles in both tumor angiogenesis and cellular proliferation. Sunitinib binds at the ATP binding site of PDGFR & VEGFR, peventing the receptor kinase from binding ATP and phosphorylating their respective tyrosine target residues. Inhibition of PDGFR and VEGFR results in reduced tumor vascularization and cancer cell death. Sunitinib is also an inhibitor of KIT, a cytokine receptor inhibitor. Mutations of the KIT gene, often resulting in overexpression are associated with most gastrointestinal stromal tumors.[19] is at equilibrium between two predominant confirmations, the active conformation and the autoinhibited inactive conformation. In its active conformation, KIT binds to stem cell factors, upon which KIT dimerizes and transmits second messenger signals ultimately resulting in cell survival and proliferation. In its inactive conformation, the "DFG Triad" of KIT, , is in the "out" position, with Phe 811 occupying the ATP binding site, preventing phosphorylation and signaling. by preferentially binding and stabilizing the autoinhibited inactive conformation of KIT (IC50 for Sunitinib is 40nM for inactive conformation and 21,000nM for active conformation). KIT binds Sunitinib using residues Lys 809, Val 603, Ala 621, Tyr 672, Cys 673, Leu 595, Cys 674, Gly 676, Leu 799, Glu 671 & Thr 670, locking the inhibitor in place and stabilizing the receptor in the inactive state.[20]
See also Bevacizumab.
See also Receptor
