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Bivalent inhibitors that target the polo-box domain in polo-like kinase 1

Wednesday, September 13, 2017 — Poster Session I

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • K Tsuji
  • D Hymel
  • TR Burke
  • Jr


The polo-like kinase 1 (Plk1) is a serine/threonine specific kinase that is a master regulator of mitosis. Over-expression of Plk1 occurs in certain cancer cells and in these cells mitotic arrest and subsequent apoptosis can be caused by inhibition of Plk1 function. There are highly potent inhibitors of Plk1, which compete with the binding of ATP at the N-terminal kinase domain (KD) and some of them have reached clinical trials. However, limiting cytotoxicity has been observed, which may potentially be due to off-target effects that arise from the high homology found among ATP-binding sites throughout the kinome. This makes it highly challenging to develop selective Plk1 kinase inhibitors. Plk family members are distinguished by the presence of unique C-terminal polo-box domains (PBDs). One function of PBDs is to modulate Plk1 kinase activity through intramolecular interactions with the KD. It also has been reported that over-expression of the Plk1 PBD prevents the formation of normal bipolar spindles and results in mitotic arrest. Therefore, inhibitors that simultaneously target both the KD and PBD domains could provide highly selective and potent inhibitors of Plk1. As reported herein, we have discovered bivalent PBD-binding inhibitors, which can show up to two-orders of magnitude affinity enhancement relative to the best previously disclosed PBD-binding inhibitors.

Category: Chemical Biology