Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells

Scharow, Andrej; Raab, Monika; Saxena, Krishna; Sreeramulu, Sridhar; Kudlinzki, D.; Gande, S.L.; Dötsch, Christina; Kurunci‐Csacsko, Elisabeth; Klaeger, Susan; Küster, Bernhard; Schwalbe, Harald; Strebhardt, Klaus; Berg, Thorsten

doi:10.1021/acschembio.5b00565

Cited by 56 publications

(67 citation statements)

References 30 publications

(68 reference statements)

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“…Poloxin and thymoquinone can block the correct orientation of PLK1 , thereby preventing the mitosis of cancer cells [126]. A recent study showed that Poloxin-2, an optimized analogue of poloxin, has significantly improved potency and selectivity over poloxin in inducing mitotic arrest and apoptosis in cultured human cancer cells [128].…”

Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

348

269

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Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structural characteristics, its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy.

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Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

348

269

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“…In an effort to further improve the efficacy of Poloxin, recently, Scharow and colleagues reported identification of the optimized analog Poloxin-2, which was shown to have significantly improved potency and selectivity over Poloxin (72). Poloxin-2 arrests mitosis in human tumor cell lines and induces apoptosis at lower micromolar concentrations (IC50=1.36 umol/L), as compared with the IC50 of 4.8 umol/L of its predecessor (70).…”

Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

328

272

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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“…Moreover, we showed that TQ and Poloxin, compounds that provided the first proof of concept for PBD inhibition by non-peptide small molecules are also alkylators of nucleophilic amino acid side chains. The potential of Poloxin to act as an alkylator on the PBD was proposed based on SAR in a recent study, but protein alkylation by Poloxin was not demonstrated52.…”

Section: Discussionmentioning

confidence: 99%

Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay

Normandin

Lavallée

Futter

et al. 2016

Sci Rep

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Polo-like kinase 1 (Plk1) plays several roles in cell division and it is a recognized cancer drug target. Plk1 levels are elevated in cancer and several types of cancer cells are hypersensitive to Plk1 inhibition. Small molecule inhibitors of the kinase domain (KD) of Plk1 have been developed. Their selectivity is limited, which likely contributes to their toxicity. Polo-like kinases are characterized by a Polo-Box Domain (PBD), which mediates interactions with phosphorylation substrates or regulators. Inhibition of the PBD could allow better selectivity or result in different effects than inhibition of the KD. In vitro screens have been used to identify PBD inhibitors with mixed results. We developed the first cell-based assay to screen for PBD inhibitors, using Bioluminescence Resonance Energy Transfer (BRET). We screened through 112 983 compounds and characterized hits in secondary biochemical and biological assays. Subsequent Structure-Activity Relationship (SAR) analysis on our most promising hit revealed that it requires an alkylating function for its activity. In addition, we show that the previously reported PBD inhibitors thymoquinone and Poloxin are also alkylating agents. Our cell-based assay is a promising tool for the identification of new PBD inhibitors with more drug-like profiles using larger and more diverse chemical libraries.

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Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells

Cited by 56 publications

References 30 publications

PLK1, A Potential Target for Cancer Therapy

PLK1, A Potential Target for Cancer Therapy

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay

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