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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, 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.
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.
Laccase-Mediated Synthesis of Novel Antibiotics and Amino Acid Derivatives
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
A further example of a homodimerization is the laccase-mediated reaction of tyrosol (Chakroun et al., 2013). After the formation of an ortho-para C–C/C–O linked product the aliphatic side chain of one monomer reacts in an intramolecular coupling reaction. The dimerization product can be described as homomolecular dimer type IV because there are only two intermolecular bonds between the two monomers.
F11R/JAM-A: why do platelets express a molecule which is also present in tight junctions?
Published in Platelets, 2023
Piotr Kamola, Anna Babinska, Tomasz Przygodzki
As mentioned above, F11R/JAM-A molecules are capable of forming homodimers. This homodimerization occurs in cis-configuration when the dimer is formed by the molecules located in the same cell (Figure 2b). The molecules can also interact in the trans-configuration when they are located on the membrane of two adjacent cells20 (Figure 2c). It is not clear whether cis-homodimerization is required for trans-homophilic interactions. Some data suggest that monomeric F11R/JAM-A can also interact with its counterpart on an adjacent cell.20 The sites responsible for cis- and trans-homophilic interactions lay in distinct parts of D1 domain of the molecule.20 Both types of interactions are believed to be associated with the function of the protein which will be described further.
Rationale for IL-37 as a novel therapeutic agent in inflammation
Published in Expert Review of Clinical Immunology, 2022
Claudia A. Nold-Petry, Marcel F. Nold
As a powerful roadblock of inflammatory responses, IL-37 function must be tightly regulated to avoid excessive suppression of innate and adaptive immunity. For example, in mice transgenic for IL-37 (IL-37tg), only little IL-37 protein is detectable under steady-state conditions despite the transgene’s constitutively active CMV promoter; abundance only increases upon inflammatory challenge [1,5,8]. In addition to an mRNA instability element, such regulation is achieved by homodimerization. Cytokine multimerization is common, but in most cases enables signaling. In contrast, the bioactivity of the head-to-head homodimer that is readily assembled by IL-37 molecules even at low concentrations is substantially lower than that of IL-37 monomers [3,11]. This rare structure–function relationship can be exploited by mutating tyrosine in position 85 to alanine, thus preventing dimerization and generating recIL-37 with considerably enhanced bioactivity [3]. To further improve drug-like properties, this IL-37 variant can be fused with an Fc-protein [12].
Challenges with matrix metalloproteinase inhibition and future drug discovery avenues
Published in Expert Opinion on Drug Discovery, 2021
The early broad-spectrum inhibitors, the selective ones and the inhibitors following a polypharmacology approach all have in common to interact with the catalytic domain of the target enzymes. Nevertheless, there is evidence that interaction with the C-terminal hemopexin-like domain, present in all but three MMPs, is a valuable alternative, given its involvement in substrate recognition and other functions such as proMMP activation or homodimerization for cancer cell migration. The activation of proMMP-2 depends on a cascade mediated by MMP-14. Surface bound MMP-14 binds TIMP-2 to form a receptor to which proMMP-2 binds with its hemopexin-like domain. In this state, nearby located MMP-14 cleaves the pro domain to release active MMP-2[130,131]. For both, MMP-9 and MMP-14, homodimerization is achieved via the respective hemopexin-like domain, which then triggers cancer cell migration[132,133].