TY - JOUR
T1 - Optimized Plk1 PBD Inhibitors Based on Poloxin Induce Mitotic Arrest and Apoptosis in Tumor Cells
AU - Scharow, Andrej
AU - Raab, Monika
AU - Saxena, Krishna
AU - Sreeramulu, Sridhar
AU - Kudlinzki, Denis
AU - Gande, Santosh
AU - Dötsch, Christina
AU - Kurunci-Csacsko, Elisabeth
AU - Klaeger, Susan
AU - Kuster, Bernhard
AU - Schwalbe, Harald
AU - Strebhardt, Klaus
AU - Berg, Thorsten
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/11/20
Y1 - 2015/11/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84947923877&partnerID=8YFLogxK
U2 - 10.1021/acschembio.5b00565
DO - 10.1021/acschembio.5b00565
M3 - Article
C2 - 26279064
AN - SCOPUS:84947923877
SN - 1554-8929
VL - 10
SP - 2570
EP - 2579
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 11
ER -