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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The first agent of this class to be approved was the HER2-specific monoclonal antibody trastuzumab (HerceptinTM) which was developed by Genentech/Roche and approved in 1998. It demonstrated a clear clinical benefit in HER2-positive breast cancer and is now widely used in this disease. However, resistance to trastuzumab occurs, so other related therapeutics have been developed to address this problem. For example, pertuzumab (PerjetaTM) is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer. It was the first-in-class HER dimerization inhibitor that works by inhibiting the dimerization of one type of HER2 receptor with another, thus preventing them from signaling to promote cell growth and proliferation. Discovered and developed by Genentech, it was first approved by the FDA in 2012. An alternative approach by Genentech involved the conjugation of a highly cytotoxic small molecule (i.e. a “payload”) to trastuzumab via a cleavable chemical linker to form an Antibody-Drug Conjugate (ADC). First approved by the FDA in 2013, this agent, trastuzumab emtansine (KadcylaTM) delivers the highly cytotoxic tubulin-interactive emtansine payload to HER2-positive tumor cells, a strategy that can be effective in patients resistant to trastuzumab alone. Trastuzumab (HerceptinTM), pertuzumab (PerjetaTM), and trastuzumab emtansine (KadcylaTM) are described in detail in Chapter 7.
Development of an Oligodeoxynucleotide Pharmaceutical for the Treatment of Human Leukemia
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Alan M. Gewirtz, Deborah Lee Sokol
Recently, a putative leucine zipper structure was described within the amino terminal portion of Myb's carboxy terminal domain (Kanei-Ishii et al., 1992). Leucine zippers, such as those found in the transcription factors Jun, Fos, and Myc are thought to facilitate the protein-protein interactions which permit heterodimerization of DNA binding proteins. Such dimerization is thought to play a key role in regulating the transcriptional activity of these factors. A Myb dimerizing binding partner has yet to be identified but Myb-Myb homodimerization, which likely occurs through its leucine zipper, does lead to loss of DNA binding and transactivation ability (Nomura et al., 1993). Accordingly, one could reasonably postulate that Myb driven transactivation and/or transformation might be regulated by the binding of additional protein partners in the leucine zipper domain (Kanei-Ishii et al., 1992). Alternatively, loss of the ability of Myb to dimerize with a putative regulatory partner might also contribute, directly of indirectly, to cellular transformation and leukemogenesis. Point mutations in the Myb negative regulatory domain might be one mechanism for bringing about such a loss (Kanei-Ishii et al., 1992). Finally, interaction (not physical dimerization) with other nuclear binding proteins such as the CCAAT enhancer binding protein (C/BEP) (Burk et al., 1993), and the related myeloid nuclear factor NF-M (Ness et al., 1993) may also regulate Myb's transactivation or repressor functions.
Oncogenes and tumor suppressor genes
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
S. Giordano, S. Corso, P. Conrotto
Several types of mutations have been identified that lead to constitutive activation of receptors, which transmit a growth signal in the absence of the ligand (Figure 8). In some cases these mutations can induce constitutive dimerization, as a consequence of ligand-independent dimerization. This has been shown, for example, in the case of the RET oncogene in multiple endocrine neoplasia type 2. In other cases, activation can be due to mutations located in the tyrosine kinase domain, responsible for a conformational change of the kinase domain toward an active conformation. This is the case, for example, for Kit and Met genes in gastro-intestinal stromal tumors and hereditary papillary renal carcinomas, respectively. Another mechanism for generating an oncoprotein receptor is loss of sequence coding for the extracellular portion and fusion with a sequence containing a dimerization motif; this happens in the case of the trk and ret genes in thyroid tumors.
Insights into the operational model of agonism of receptor dimers
Published in Expert Opinion on Drug Discovery, 2022
So far, presented models described constitutive dimers that exist in the absence of a ligand and a ligand does not affect their formation. To fully describe the system of dynamic dimers means to introduce one (homodimers) or two (heterodimers) additional receptor species and a dimerization constant (Supplementary Information Figure S3) [26]. In the case of ligand-modulated dimerization, the model has to be extended with dimerization cooperativity factors. In the case of a ligand-modulated heterodimer, the system consists of three inactive species RA, RB and RARB, five active species ARA, RBA, ARARB, RARBA and ARARBA with various operational efficacies, two equilibrium dissociation constants KA and KB, one dimerization constant KD and four cooperativity factors α, δ, ε and ζ. An exact analysis of behavior, like a derivation of relations among parameters and quantifiers, of the deterministic model of such a complex system is impossible. Even in much simpler OMARD, only approximate solutions to equations A67 and A84 exist.
TPD7 inhibits the non-small cell lung cancer HCC827 cell growth by regulating EGFR signalling pathway
Published in Journal of Chemotherapy, 2022
Xiaoyan Zhang, Hongjun Zhang, Gangqiang Qi, Xing Gu, Yanjun Zhao, Jie Zhang
Epidermal growth factor receptor (EGFR), the member of HER family receptors, has been confirmed as a tumorigenic driving factor of NSCLC, especially the activation of EGFR mutation and its specific tyrosine kinase receptor inhibitors (TKIs) inhibition can produce a significant tumour response [4]. EGFR is structurally composed of an extracellular ligand binding domain, a transmembrane domain, a tyrosine kinase domain, and a non-structural c-terminal tail containing receptor autophosphorylation sites. Ligands such as EGF bind to the extracellular domain of EGFR, causing conformational changes and promoting the homo- and heterodimerization of EGFR. Dimerization induces activation of receptor tyrosine kinase activity, leading to autophosphorylation of C-terminal tyrosine [5]. The phosphorylation of EGFR activates the downstream effectors such as PI3K/AKT and MEK/ERK, which stimulate cell growth, survival, migration, and interrupts programmed cell death [6,7]. Therefore, the development of EGFR targeted drugs is effective method in the treatment of NSCLC [8,9].
Editorial: structure–function relationships of tyrosine kinase- and tyrosine phosphatase-linked receptors in platelets and megakaryocytes
Published in Platelets, 2021
Platelets are regulated by two major classes of surface receptors which can be distinguished by the number of transmembrane chains. Seven transmembrane receptors signal through heterotrimeric G proteins and are regulated by so-called soluble agonists. The family of G protein-coupled receptors is divided into stimulatory receptors, which regulate Gq, G12/13 and Gi family G proteins, and inhibitory receptors, which regulate Gs family G proteins. Examples include the receptors for ADP, thrombin, and prostacyclin. The group of single transmembrane receptors is much larger and diverse, with a greater range of functions including adhesion, signaling, and membrane organization. Several of these proteins form larger complexes composed of distinct chains as exemplified by the major signaling receptor for collagen, the GPVI-Fc receptor chain (FcR) complex, with GPVI harboring the binding site for collagen, and FcR the signaling arm. Regulation of many single transmembrane proteins is mediated through dimerization and higher order clustering, rather than through a conformational change.