Abstract:The polo-box domain (PBD) of Plk1
is a promising target for cancer
therapeutics. We designed and synthesized novel phosphorylated macrocyclic
peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL.
The inhibitory activities of 16e on Plk1-PBD is >30-fold
higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis
of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts … Show more
“…Different compounds have been synthesized ( 6 , 125 , 126 ). At the moment there are more than ten available PLK1 specific inhibitors, four of which (BI2536, BI6727-volasertib, GSK461364 and NMS-1286937-onvasertib- all ATP competitors) have reached the clinical trials (listed in Table 1 ).…”
Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine/threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its important involvement in regulating the G2/M checkpoint, in DNA damage and replication stress response, and in cell death pathways. PLK1 expression is tightly spatially and temporally regulated to ensure its nuclear activation at the late S-phase, until the peak of expression at the G2/M-phase. Recently, new roles of PLK1 have been reported in literature on its implication in the regulation of inflammation and immunological responses. All these biological processes are altered in tumors and, considering that PLK1 is often found overexpressed in several tumor types, its targeting has emerged as a promising anti-cancer therapeutic strategy. In this review, we will summarize the evidence suggesting the role of PLK1 in response to DNA damage, including DNA repair, cell cycle progression, epithelial to mesenchymal transition, cell death pathways and cancer-related immunity. An update of PLK1 inhibitors currently investigated in preclinical and clinical studies, in monotherapy and in combination with existing chemotherapeutic drugs and targeted therapies will be discussed.
“…Different compounds have been synthesized ( 6 , 125 , 126 ). At the moment there are more than ten available PLK1 specific inhibitors, four of which (BI2536, BI6727-volasertib, GSK461364 and NMS-1286937-onvasertib- all ATP competitors) have reached the clinical trials (listed in Table 1 ).…”
Polo-like kinase 1 (PLK1) is the principle member of the well conserved serine/threonine kinase family. PLK1 has a key role in the progression of mitosis and recent evidence suggest its important involvement in regulating the G2/M checkpoint, in DNA damage and replication stress response, and in cell death pathways. PLK1 expression is tightly spatially and temporally regulated to ensure its nuclear activation at the late S-phase, until the peak of expression at the G2/M-phase. Recently, new roles of PLK1 have been reported in literature on its implication in the regulation of inflammation and immunological responses. All these biological processes are altered in tumors and, considering that PLK1 is often found overexpressed in several tumor types, its targeting has emerged as a promising anti-cancer therapeutic strategy. In this review, we will summarize the evidence suggesting the role of PLK1 in response to DNA damage, including DNA repair, cell cycle progression, epithelial to mesenchymal transition, cell death pathways and cancer-related immunity. An update of PLK1 inhibitors currently investigated in preclinical and clinical studies, in monotherapy and in combination with existing chemotherapeutic drugs and targeted therapies will be discussed.
“…Some of these molecules are capable of binding to the active pocket within the polo-box domain (PBD), a crucial region for PLK1 activation. 43,44 However, challenges in developing these molecular drugs for clinical use include issues related to specificity and dose-limiting toxicity. 45 Degradable BP presents an attractive candidate as a PLK1 inhibitor due to the phosphate groups generated during degradation.…”
Molecular dynamics simulations are performed to reveal the degradation-dependent bioactivity of black phosphorus in suppressing the centrosome polo-like kinase 1.
“…The Plk1 is abundantly expressed in tumor cells, but not in normal cells, and is also associated with adverse prognosis, metastatic potential and cancer progression. 30,31 In this study, we employed the conjugation of "tripleinteraction" angiopep-2 decorated novel cubs systems (Ang-cubs-(GNA + PLHSpT)). The physicochemical properties of Ang-cubs-(GNA + PLHSpT), including particle size, Zeta potential, transmission electron microscopy (TEM), entrapment efficiency (EE%), drug loading (DL%), differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS) and ligation efficiency were comprehensively investigated.…”
Section: Introductionmentioning
confidence: 99%
“…The Plk1 is abundantly expressed in tumor cells, but not in normal cells, and is also associated with adverse prognosis, metastatic potential and cancer progression. 30,31 Figure 1.Structure of GNA (a) and PLHSpT (b).…”
3Glioblastoma multiforme is the most aggressive malignant brain tumor. However, the treatment of glioblastoma multiforme faces great challenges owing to difficult penetration of the blood-brain barrier. Therefore, more effective treatment strategies are desired quite urgently. In our study, a dual-targeting drug delivery system for co-loading with hydrophobic Gambogenic acid and hydrophilic PLHSpT was developed by cubosomes with angiopep-2 decorating. The Ang-cubs-(GNA + PLHSpT) was prepared by high-temperature emulsification-low-temperature solidification demonstrating excellent physical properties.Transmission electron microscopy revealed that Ang-cubs-(GNA + PLHSpT) was nearly spherical with a “core-shell” double-layer structure. Differential scanning calorimetry suggested that a new phase was formed. Small-angle X-ray scattering also verified that Ang-cubs-(GNA + PLHSpT) retains the Pn3m cubic. Moreover, laser confocal indicated that Ang-cubs-(GNA + PLHSpT) was capable of crossing BBB via binding to lipoprotein receptor-related protein-1, likely suggesting the potential tumor-specific targeting characteristic. Compared to free drug and cubs-(GNA + PLHSpT), Ang-cubs-(GNA + PLHSpT) was easily taken up by C6 cell and exhibited better anti-glioma effects in vitro. Importantly, GNA and PLHSpT co-loaded Ang-cubs could suppress tumor growth and significantly prolong survival in vivo. In conclusion, Ang-cubs-(GNA + PLHSpT) acts as a new dual-targeting drug delivery system for the treatment of GBM.
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