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Antitubulin Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Figure 4.26 shows the processes involved in mitosis, along with specific druggable protein targets. These include: Polo-like kinases (e.g., PLK1 and PLK3): These enzymes are involved in centromere maturation and formation of the mitotic spindle. They are also active in the exit from mitosis and the separation of sister chromatids during anaphase. PLK1 is an early trigger for G2/M transition and also supports the functional maturation of the centrosome in late G2/early prophase along with the establishment of the bipolar spindle. Another role of PLK1 is to phosphorylate and activate CDC25C, a phosphatase that dephosphorylates and activates the Cyclin B/CDC2 complex.Kinesin spindle protein (KSP): This protein establishes mitotic spindle bipolarity through driving centrosome separation.Centromeric protein E (CENPE): This protein is required for accurate congression of the chromosomes at metaphase.Aurora kinase A: This kinase is important for centrosome maturation and separation during early prophase.Aurora kinase B: This kinase is a member of the chromosomal passenger complex (CPC) and is involved in histone H3 phosphorylation, chromosomal condensation, chromosomal alignment on the metaphase plate, bipolar centromere-microtubule attachments, spindle checkpoint, and function of the cytokinesins.
Inhibitors of the PLK1 polo-box domain: drug design strategies and therapeutic opportunities in cancer
Published in Expert Opinion on Drug Discovery, 2023
Jessy M. Stafford, Michael D. Wyatt, Campbell McInnes
Rubner et al. added a bulky hydrophobic adamantyl tag through acylation of Poloxin2 [82,112]. The positioning of the tag was based on mechanistic considerations attributable to sites of nucleophilic attack to ensure that the hydrophobic tail will be displayed on the protein surface after compound binding. The concept of hydrophobic tagging is that once bound to the protein of interest, the adamantyl group would be recognized by chaperones as a misfolded protein which will in turn lead to recruitment of proteasomes for degradation. As proof of concept, Poloxin2-HT was able to induce degradation of PLK1 selectively in cellular assays while at the same time having minimal impact on the levels of PLK2 and PLK3. Mitotic arrest with a monastral spindle phenotype was observed, an effect indicative of complete loss of PLK1 function. Indeed, western blotting confirmed that the PLK1 protein is targeted for degradation indicating one of the first successes in applying hydrophobic tagging to a protein-protein interaction inhibitor. Compounds with low molecular weight hydrophobic tags are proposed to have a degradation mechanism of action different from that of PROTAC chimeric ligands and are also more likely to be cell permeable and metabolically stable compared to conjugates of ubiquitin ligase recruiting ligands [112]. In a follow-up study, modification of the adamantyl tag with an extended alkyl chain to generate Poloxin2-HT+ (Table 2) resulted in better efficacy in terms of potent and selective degradation of PLK1 and induction of apoptosis [113].
PLK4: a link between centriole biogenesis and cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Radhika Radha Maniswami, Seema Prashanth, Archana Venkataramana Karanth, Sindhu Koushik, Hemalatha Govindaraj, Ramesh Mullangi, Sriram Rajagopal, Sooriya Kumar Jegatheesan
Mammalian cells express five PLK family members (PLK1, PLK2, PLK3, PLK4, and PLK5) [16]. All PLKs except PLK5 have a conserved N-terminal kinase catalytic domain and a C-terminal non-catalytic polo-box domain containing two or three polo boxes involved in binding to substrates [17]. These PLKs are mainly characterized by their polo-box domain, which mediates protein interactions [18]. Studies have revealed that there are no other protein categories bearing the polo box domain, suggesting that PLKs possess unique functions during the cell cycle [19,20]. PLK 1–4 are mainly involved in centrosome biology besides regulating mitosis, cytokinesis, and cell cycle checkpoints, while PLK5 lacks the kinase domain and thus does not seem to have a role in cell cycle progression [21]. PLK1 regulates a number of processes throughout the cell cycle, including centrosome maturation [22], mitotic entry [23,24], chromosome segregation [25–27], and cytokinesis [28,29]. PLK2 regulates centrosome maturation, genotoxic stress response, and neuron differentiation [13,30]. PLK3 is involved in DNA replication [31,32] and might respond to genotoxic stress through p53-dependent pathway leading to cell cycle arrest and apoptosis [33–36]. PLK5 is a pseudo kinase mainly involved in neuronal activities and functions as a tumor suppressor in brain cancer [21].