Multiple modular bindings discussed here may also help diminish the probability of developing drug resistance. Concluding remarks Given the significant level of side effects associated with conventional MT-targeting anticancer therapeutics, developing an inhibitor against a mitosis-specific and cancer-cell-addicted target such as Plk1 may represent a promising strategy for the generation of a cancer-cell-specific therapeutic agent. severe and dose-limiting side effects that arise as the consequence of indiscriminately disrupting widespread MT functions, not only in actively dividing TRICK2A mitotic cells but also in non-dividing interphase cells. Thus, over the past decade, a high level of interest has been drawn to targeting a variety of mitosis-specific proteins in order to develop agents that can specifically disrupt the mitotic progression of highly proliferative cancer cells. These proteins include protein kinases (polo-like BTT-3033 kinase 1 [Plk1] 2 and Aurora A 3), motor proteins (CENP-E 4, 5 and Eg5 6), DNA-damage checkpoint proteins (Chk1 and Chk2 7), and components of the ubiquitin proteasome pathway (APC/Cdc20 and the proteasome 8, 9). Among these endeavors, anti-Plk1 drug discovery has reached an advanced stage of development that merits reflection on its progress. In this short review, we will summarize recent advances and future directions toward developing therapeutics against one of the most appealing anti-cancer drug targets, Plk1. Plk1 as an anti-mitotic target Plk1 belongs to the polo subfamily of Ser/Thr protein kinases (collectively, Plks) and plays a key role at multiple stages of mitotic progression 10. Plk1 is composed of the em N /em -terminal catalytic domain and the em C /em -terminal non-catalytic polo-box domain (PBD) ( Figure 1). The cooperative action of these two domains is critical for Plk1 to regulate diverse mitotic processes 11. Not surprisingly, Plk1 is overexpressed in a wide spectrum of human cancers 12, and its overexpression is thought to promote genomic instability and tumorigenesis 13C 15. In addition, upregulated Plk1 activity appears to be closely associated with the aggressiveness and poor prognosis of these cancers 16, 17. Other studies have shown that various tumor cellsbut not their isogenic normal cellsare addicted to Plk1 overexpression for his or her viability 18C 20. Since reversing addicted protein functions has proven to be an attractive strategy to selectively destroy tumor cells 18, 21C 23, addiction to overexpressed Plk1 exacerbates the vulnerability of malignancy cells to Plk1 interrogation. Therefore, focusing on Plk1 may permit the induction of cancer-cell-selective mitotic block and apoptotic cell BTT-3033 death in Plk1-addicted cancers 24. Because human being cancers are frequently sluggish growing, inhibiting a cancer-addicted target, such as Plk1, could be particularly effective in achieving the full therapeutic potential of an anti-mitotic agent. Open in a separate window Number 1. Schematic diagram of human being polo-like kinase 1 (Plk1).The numbers indicate the positions of the amino acid residues in human being Plk1. Promising Plk1 ATP-competitive inhibitors and their limitations Focusing on the catalytic activity of a protein kinase has been the predominant method of generating kinase inhibitors. Accordingly, a large number of ATP-competitive inhibitors directed against the catalytic activity of Plk1 have been developed and tested under numerous preclinical and medical settings BTT-3033 24 ( Number 2). Among them, volasertib (a dihydropteridinone derivative; Boehringer Ingelheim) is definitely widely regarded BTT-3033 as the most advanced inhibitor with this class, exhibiting potent anti-tumor activities in multiple nude mouse xenograft models 25. Volasertib has also shown significant medical efficacies against advanced solid and hematological cancers in phase I/II clinical tests 26C 30. However, the initial end result of its phase III clinical tests, BTT-3033 performed having a cohort of seniors acute myeloid leukemia individuals, turned out to be less than adequate (the 21st Annual Congress of the Western Hematology Association, 2016). In addition, several other ATP-competitive inhibitors, such.