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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
ErbB-1 (EGFR) and ErbB-2 are receptor kinase targets over-expressed in a number of tumor types, including breast, lung, pancreas, colon, and head and neck cancers. Varlitinib (Figure 6.21) was identified by Aslan Pharmaceuticals as a novel orally available ErbB family inhibitor that, unlike other approved ErbB inhibitors at the time, targeted all members of the ErbB family including ErbB3, either directly or indirectly, and thus had potential advantages in treating tumors that signal through multiple ErbB pathways. In preclinical studies it was shown to be a potent reversible inhibitor of EGFR, HER2, and HER4, and was active as both a single agent and in combination with trastuzumab (HerceptinTM), capecitabine (XelodaTM), and docetaxel (TaxotereTM) in tumor models signaling through multiple ErbB pathways. Structure of varlitinib (ASLAN001, ARRY-543).
Additive and Synergistic Interactions of Monoclonal Antibodies and Immunotoxins Reactive with Breast and Ovarian Cancer
Published in Ronald H. Goldfarb, Theresa L. Whiteside, Tumor Immunology and Cancer Therapy, 2020
Robert C. Bast, Fengji Xu, Yinhua Yu, Jennie Crews, Yair Argon, Yaron Lidor, Andrew Berchuck, Cinda M. Boyer
When expression of EGFR was studied in human ovarian cancers, 77% of 87 neoplasms could be stained with the 225 antibody.(10) The prognosis of patients whose tumors expressed EGFR was worse than the prognosis of patient’s whose tumors did not express EGFR. In subsequent studies of human ovarian cancer, expression of different oncogenes was studied by Northern transfers.(11) Expression of erbB could not be detected, but 86% of 22 cancers expressed HER-2/neu. In addition, HER-2/neu can be amplified and overexpressed in ovarian cancers.(12,13) When frozen sections of epithelial cancer were stained with the TA1 antibody against the extracellular domain of HER-2/neu, approximately two-thirds of cancers have low, but detectable, levels of antibody binding.(12) In one-third of ovarian cancers, there was marked overexpression of HER-2/neu and this was associated with a significantly worse prognosis. Patients whose tumors overexpressed p185 had a median survival of approximately 16 months, whereas those individuals whose tumors had normal p185 expression had a median survival of some 32 months.
Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Anthony J. Demetris, J.G. Lunz, Vladimir Subbotin, Tong Wu, Isao Nozaki, Sarah Contrucci, Xia Yin
The ErbB receptor family of type I receptor tyrosine kinases has four members: EGFR (or ErbB1/Her1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. All family members have in common an extracellular ligand-binding domain, a single transmembrane region and a cytoplasmic protein tyrosine kinase domain.98,99 Ligand binding leads to receptor aggregation in coated pits and vesicles, which appears to be essential for signal propagation. Receptor aggregation also forms the basis for homo- and heterodimeric interactions within the ErbB family of proteins.98,99 Trans-phosphorylation of tyrosine residues in multimeric complexes results in tyrosine phosphorylation of a number of intracellular substrates including PLC-(gamma), the GTPase-activating protein (GAP) of the ras proto-oncogene and lipocortin I (Fig. 3).98,99 Many of these proteins interact with the activated EGFR through Src homology 2 (SH2) domains, sequences of about 100 amino acids that specifically recognize phosphotyrosines. Readers interested in more detail about the EGF signaling pathways in general and liver reactions, in specific, are referred elsewhere.98,99
Design, synthesis and biological evaluation of a series of dianilinopyrimidines as EGFR inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Longjia Yan, Qin Wang, Li Liu, Yi Le
EGFR is a receptor for an epithelial growth factor (EGF) cell proliferation and signal transduction11. It belongs to a family of ErbB receptors, which includes EGFR (HER1 or ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4). EGFR plays an essential role in regulating cell growth, proliferation and differentiation and other physiological activities of various cancer cells, which is an important target for anti-cancer drug research12–14. As shown in Figure 1, lots of EGFR inhibitors such as Gefitinib, Afatinib, and Osimertinib have been approved in the market, which significantly improves the clinical treatment of NSCLC patients15–17. However, with the continuously emerging resistance of EGFR inhibitors, the development of new EGFR inhibitors has become a hot topic in drug discovery18–20.
The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro
Published in International Journal of Neuroscience, 2021
Xizhong Yang, Cuijie Ji, Xinyue Liu, Chaoqun Zheng, Yanxin Zhang, Ruowu Shen, Zangong Zhou
Neuregulin-1 (NRG-1) is a member of the family of regulatory proteins that contain the EGF (epidermal growth factor)-like domain. It is a type of transmembrane protein that regulates the growth and development of glial cells and neurons [8]. The functional receptor of NRG is the ErbB receptor, which includes ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. ErbB is a member of the EGF receptor family of transmembrane tyrosine kinases. Both ErbB2 and ErbB3 receptors are required in the development of SCs, but these two receptors have different effects; ErbB3 can bind with extracellular ligands with high affinity even though it is inactive, while ErbB2 tyrosine kinase activity can activate downstream signaling [9]. Sox10 belongs to the Sox family, members of which contain a DNA binding domain that is similar to the HMG (high mobility group) domain of the SRY transcription factor family [10]. The structure of Sox10 is highly conserved, especially the structure of its functional domains, such as the N-terminal to C-terminal dimerization domain, the HMG domain, and the protein interaction (K2) domain [11]. The Sox gene family is involved in stem cell maintenance, cell differentiation and tissue formation. Sox10 plays an important role in the formation of the neural crest and peripheral nervous system, the maturation and terminal differentiation of SCs, and the differentiation of melanocytes. Sox10 and Oct6 have synergistic effects on the differentiation and development of SCs [12]. In addition, in the central nervous system and the peripheral nervous system, Sox10 is highly expressed in neural crest cells and glial cells.
Cholangiocarcinoma: bridging the translational gap from preclinical to clinical development and implications for future therapy
Published in Expert Opinion on Investigational Drugs, 2021
Leonardo Baiocchi, Keisaku Sato, Burcin Ekser, Lindsey Kennedy, Heather Francis, Ludovica Ceci, Ilaria Lenci, Domenico Alvaro, Antonio Franchitto, Paolo Onori, Eugenio Gaudio, Chaodong Wu, Sanjukta Chakraborty, Shannon Glaser, Gianfranco Alpini
The ERBB family comprises four tyrosine kinase receptors strictly related in structure with Epidermal Growth Factor Receptor (EGFR) formerly also known as ERBB-1. Neoplastic mutation of this system determines the increased downstream activity of mitogen-activated protein kinase (MAPK-ERK) and/or phosphatidylinositol-4,5-bisphosphate 3-kinase/mammalian target of rapamycin (PI3k-mTOR) pathways and favors EMT phenotypes [47,48]. EGFR mutation is reported with a similar percentage (around 3%) in all CCAs while ERBB-2 (also known as HER-2) is more frequent (around 18%) in non-intrahepatic CCAs [30]. Since the ligand for HER-2 has not been identified so far, this receptor is thought to function after heterodimerization with other members of its family. Among them, HER-3 seems to be the preferred candidate since HER-2/HER-3 dimer has the strongest effects. In this perspective, the differential expression of HER-2 and -3 in biliary tract cancer is considered with interest, being a possible biomarker of prognosis and response to therapy [49]. The ERBB inhibitors may be divided into two specific classes: (1) ligand-blocking monoclonal antibodies and (2) tyrosine-kinase inhibitor (TKI). Preclinical data were encouraging on the use of these molecules in CCA [50], also in combination therapy [51]. However, clinical trials based on the suppression of ERRB in CCA, did not replicate the positive favorable in vitro and in vivo preliminary results [52,53]. A trial combining Varlitinib and Capecitabine for metastatic biliary cancer is currently ongoing (NCT03093870).