Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The type I RTK kinase family consists of four distinct but closely related receptors: epidermal growth factor receptor 1 (EGFR, ErbB1, Her1), 2 (HER2, ErbB2), 3 (Her3, ErbB3), and 4 (HER4, ErbB4). In response to the binding of various ligands, these kinases undergo heterodimerization and homodimerization, resulting in the activation of numerous growth factor signaling pathways. Therefore, inhibiting these activated pathways can lead to an antitumor effect. In a large variety of tumor types the over-expression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. For example, in gastric cancer approximately 10% of tumors have amplification of the HER2 gene. Therefore, the HER-family of receptors has been a key target for the development of anticancer therapeutics.
Epidermal Growth Factor Receptor Inhibition in Non–Small Cell Lung Cancer
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
The epidermal growth–factor receptor (EGFR, HER1) is a member of the HER family of membrane receptors (HER1–4). The other members are HER2 (also termed ErbB2 or HER2/neu), HER3 (also termed ErbB3), and HER4 (also termed ErbB4). These receptors share the same molecular structure with an extracellular, cysteine-rich, ligand-binding domain, a single α-helix transmembrane domain, and an intracellular domain with tyrosine–kinase (TK) activity in the carboxy-terminal tail (excepting the HER3) (1). The TK domains of HER2 and HER4 show an 80% homology to that of the EGFR (2). Epidermal growth factor (EGF), transforming growth factor-α (TGF-α), and amphiregulin bind exclusively to the EGFR, whereas betacellulin and epiregulin bind both EGFR and HER4. Ligand binding induces EGFR homodimerization as well as heterodimerization with other types of HER proteins (3,4). HER2 does not bind to any known ligand, but it is the preferred heterodimerization partner for EGFR after ligand-induced activation (5). EGFR/EGFR homodimers are unstable, whereas EGFR/HER2 heterodimers are stable and recycle more rapidly to the cell surface (6).
Molecular Farming Antibodies in Plants: From Antibody Engineering to Antibody Production
Maurizio Zanetti, J. Donald Capra in The Antibodies, 2002
The challenge of bringing two different antigen-binding sites together is directly related to the problem of designing multivalent rAbs and of coupling the humoral and cellular immune response [140]. The most popular application of the bispe-cific antibody concept has been in tumor therapy, where a bi-specific molecule contains a tumor-binding domain and a domain to recruit effector cells to kill the tumor [33, 141-149]. As an example, bispecific molecules can bind a tumor cell and cytotoxic or T-helper cells and trigger the desired biological response exclusively close to the tumor site. Bispecific antibodies containing an Fc region are likely to be preferred over antibody fragments, for some clinical applications, in order to obtain long serum half-life and/or to recruit effector functions. For example antibody heavy chains have been engineered for heterodimerization using sterically complementary mutations at the CH3 domain interface [150]. A "knob" mutation was first created by the replacement of a small residue by a large one (Thr366 — Trp). The hole was created by replacing a larger residue in the CH3 domain with a smaller one (Tyr407 — Thr). "Knobs into holes" engineering permitted the production of an antibody immuno-adhesin hybrid with 90% mutant yield [150].
The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella
Published in Systems Biology in Reproductive Medicine, 2023
Zhiren Liu, Yujia Guo, Xingting Chen, Chen Lin, Xinxin Guo, Mingting Jiang, Qicai Liu
Day 6 embryos with blastulation failure are suitable for the comparison. Through the transcriptome analysis of day 6 embryos, GO analysis showed that AOA had effects on the terms of ‘protein-DNA complex’, ‘nucleosome’, and ‘DNA packaging complex’. It indicated that AOA had an effect on the chromosome structure of the day 6 embryo. The change in chromosome structure can further affect transcriptional regulation and selective expression of genes. Cell differentiation depends on gene-specific expression. Therefore, cell differentiation may also be affected by AOA. It may be why the blastocysts of AOA groups had more differentiation failure cells. In addition, in the ‘protein heterodimerization activity’ term, except for the genes involved in chromosome structure, most of the rest of the genes are involved in transcriptional regulation. These genes included USF1, NFYB, METTL3, LSM6, GTF2A1, FMR1, CREB3L3, CEBPB, and BHLHE40 (Table 2 and Supplementary Table 3). METTL3 has been shown to be involved in the differentiation of embryonic stem cells (Geula et al. 2015). Therefore, AOA also has a direct effect on transcriptional regulation.
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
Many receptors, especially GPCRs, function as dimers. Dimerization affects agonist binding and functional response and enriches the pallet of possible signaling patterns, including biphasic functional responses that may even take a shape of a bell. In effect, functional-response curves are complex. However, a combination of various receptors into heterodimers brings more possible pharmacological targets varying in pharmacological properties and thus new ways for selective therapeutic targeting. Individual physiological processes are executed by a dedicated organ or tissue. As expression patterns of individual receptors vary among tissues and organs the probability of variation in heterodimerization increases. This gives a chance for tissue-specific pharmacotherapy of desired physiological functions held by the targeted tissue.
Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors
Published in Expert Opinion on Investigational Drugs, 2019
Dan Wang, Li Yang, Weina Yu, Yi Zhang
FGFR-targeted drugs have exhibited favorable clinical responses and a manageable safety profile in FGFR2 fusion-positive ICCA, advanced-stage clonal FGFR2 gastric cancer, FGFR-amplified NSCLC, and FGFR-mutant bladder, urothelial, breast, and biliary duct cancer, FGFR2-alteration bladder, urothelial, glioblastoma, urothelial, endometrial, breast, and biliary duct cancer. Structural similarities with other molecules in the FGFR family, including FGFR1 and FGFR3, limit the specificity of FGFR2-targeted therapy. Hence, further studies are required to focus on molecular alterations in FGFR2 and its activated pathway, thus facilitating better treatment outcomes with the targeted therapies. Although FGFR2 is an oncogene [137,156], it also displays tumor suppressor effects under different cellular contexts and in different isoforms [10,26,157,158]. Several studies on different FGFR2 isoforms have reported conflicting results regarding its clinical roles [26,159]. More effective methods to detect FGFR2 isoforms and their response to different interruption pathways are needed. Moreover, FGFR heterodimerization is a method of signal amplification and diversification, which enhances receptor activation and downstream signaling [160,161]. The potential for FGFR heterodimerization represents another potential obstacle, for which new methods are required to characterize heterodimerization.
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