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|Ref Type||Journal Article|
|Authors||Scharow A, Raab M, Saxena K, Sreeramulu S, Kudlinzki D, Gande S, Dotsch C, Kurunci-Csacsko E, Klaeger S, Kuster B, Schwalbe H, Strebhardt K, Berg T|
|Title||Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells.|
|Journal||ACS chemical biology|
|Date||2015 Nov 20|
|Abstract Text||Polo-like kinase 1 (Plk1) is a central regulator of mitosis and has been validated as a target for antitumor therapy. The polo-box domain (PBD) of Plk1 regulates its kinase activity and mediates the subcellular localization of Plk1 and its interactions with a subset of its substrates. Functional inhibition of the Plk1 PBD by low-molecular weight inhibitors has been shown to represent a viable strategy by which to inhibit the enzyme, while avoiding selectivity issues caused by the conserved nature of the ATP binding site. Here, we report structure-activity relationships and mechanistic analysis for the first reported Plk1 PBD inhibitor, Poloxin. We present the identification of the optimized analog Poloxin-2, displaying significantly improved potency and selectivity over Poloxin. Poloxin-2 induces mitotic arrest and apoptosis in cultured human tumor cells at low micromolar concentrations, highlighting it as a valuable tool compound for exploring the function of the Plk1 PBD in living cells.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Poloxin-2||PLK1 Inhibitor 16||Poloxin-2, an analog of Poloxin, is a small molecule inhibitor of PLK1, which may result in apoptotic activity and induction of cell-cycle arrest (PMID: 26279064).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||Poloxin-2||Preclinical - Cell culture||Actionable||In a preclinical study, human cancer cells demonstrated sensitivity to treatment with Poloxin-2 in culture, resulting in cell-cycle arrest and apoptotic induction (PMID: 26279064).||26279064|