Scharow Andrej, Knappe Daniel, Reindl Wolfgang, Hoffmann Ralf, Berg Thorsten
Leipzig University, Institute of Organic Chemistry, Johannisallee 29, 04103, Leipzig, Germany.
Leipzig University, Institute of Bioanalytical Chemistry, Center for Biotechnology and Biomedicine (BBZ), Deutscher Platz 5, 04103, Leipzig, Germany.
Chembiochem. 2016 Apr 15;17(8):759-67. doi: 10.1002/cbic.201500535. Epub 2015 Dec 4.
Polo-like kinase 1 (Plk1), a validated cancer target, harbors a protein-protein interaction domain referred to as the polo-box domain (PBD), in addition to its enzymatic domain. Although functional inhibition either of the enzymatic domain or of the PBD has been shown to inhibit Plk1, so far there have been no reports of bifunctional agents with the potential to target both protein domains. Here we report the development of Plk1 inhibitors that incorporate both an ATP-competitive ligand of the enzymatic domain, derived from BI 2536, and a functional inhibitor of the PBD, based either on the small molecule poloxin-2 or on a PBD-binding peptide. Although these bifunctional agents do not seem to bind both protein domains simultaneously, the most potent compound displays low-nanomolar activity against the Plk1 PBD, with excellent selectivity over the PBDs of Plk2 and Plk3. Our data provide insights into challenges and opportunities relating to the optimization of Plk1 PBD ligands as potent Plk1 inhibitors.
Polo样激酶1（Plk1）是一个已得到验证的癌症靶点，除了其酶结构域外，还含有一个称为polo盒结构域（PBD）的蛋白质-蛋白质相互作用结构域。尽管已经证明对酶结构域或PBD的功能抑制均可抑制Plk1，但迄今为止，尚无关于有可能靶向这两个蛋白质结构域的双功能药物的报道。在此，我们报告了Plk1抑制剂的研发情况，这些抑制剂既包含源自BI 2536的酶结构域的ATP竞争性配体，又包含基于小分子poloxin-2或PBD结合肽的PBD功能抑制剂。尽管这些双功能药物似乎不会同时结合两个蛋白质结构域，但最有效的化合物对Plk1 PBD表现出低纳摩尔活性，对Plk2和Plk3的PBD具有出色的选择性。我们的数据为优化作为有效Plk1抑制剂的Plk1 PBD配体所涉及的挑战和机遇提供了见解。
