PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

Table 2

PLK-1 PBD domain targeted inhibitors.

Compounds	Chemical class	Synonyms	IC50 value for PLK-1-PBD^a	Mechanism of action	Selectivity	Selectivity index; = b/a, = c/a, = d/a	Interacting residues	References
Thymoquinone	Isolated from Nigella sativa	EINECS 207-721-1,; NSC 2228,; p-Cymene-2,5-dione,; Thymoquinon,; Thymoquinone	1.14 ± 0.4 µM	Interrupt the PLK-1-PBD interaction in vitro and in vivo	Interacting with polo box domain and interrupt subcellular localization of PLK-1; Also inhibits phosphoser/phosphothr Chk2 FHA domain, Pin1 WW domain, phosphotyr binding src homology 2 (SH2) domain of STAT3	ND	Cys544, Arg500, Pro545, Leu546; (Homology Model)	[27, 57, 70]
Poloxin	Synthetic derivative of well-known PBD- inhibitor thymoquinone	Poloxime	PLK-1 PBD: 4.8 ± 1.3 µM	Interferes with PLK-1-PBD functions in vitro and in vivo	Poloxin inhibits other subtypes of the phosphothr/phosphoser binding domains (FHA domain of Chk2, WW domain of PIN1) and the phosphotyr-binding domains (SH2 domains of STAT1, STAT3, STAT5 and LCK), similar phenotype like PLK-1 ATP competitive inhibitor	= 3.8-fold; = 11.22 fold; = ND	Cys544, Arg500, Pro545, Leu546, Asn527, Arg507; (Homology Model)	[27, 57]
Purpurogallin (PPG)	Benzotropolone natural product derived from nutgall by RIKEN, Japan	CCRIS 8139,; EINECS 209-324-9,; NSC 35676,; Purpurogalli,; Purpurogalline,; UNII-L3Z7U4N28P	0.3 µM in; GST-pulldown; assays using PLK1 PBD as bait for; WEE1A	Inhibits; PBD-dependent; binding in vitro and; in vivo by 2-hydroxyl group	Also inhibits HIV-1 integrase, tyrosine protein kinases, Bcl-XL, BH3 peptides, prolyl endopeptidases and DNA synthesis of tumor cells; Delayed the onset of mitosis; Kinetochore localization of CENP-E inhibited, destabilized microtubules interaction	ND	His538, Lys540, Trp 414, Leu491; (Homology Model)	[27, 71]
Poloxipan	Panspecific inhibitor	NA	PLK-1-PBD: 3.2 ± 0.3 µM	Inhibits PLK-1-PBD binding manner	Poloxin inhibits other subtypes of the phosphothr/phosphoser binding domains (FHA domain of Chk2, WW domain of PIN1) and the phosphotyr-binding domains (SH2 domains of STAT1, STAT3, STAT5, and LCK)	= 0.53-fold; = 0.93 fold	ND	[72]
Aristolactam AIIIa	Derivative of natural product Aristolactam AIIIa	CCRIS 2996,; Aristolactam-aii,; Dibenz(cd,f)indol-4(5H)-one, 2-hydroxy-1-methoxy	PLK-1 = 47.5 µM; PBD = 10 µM	Inhibits kinase and PBD domain with different inhibitory concentration	Antiproliferative activity and induced mitotic arrest; Inhibits cancer cell lines as well as clinically drug resistance cell line HCT-8/V	ND	ND	[73]
MAGPMQSpTPLGAKK	Optimal phosphopeptide; sequence	PoloBoxtide	IC50 = 5 µM; Kd = 280 nM	PoloBoxtide is recognized by pincer grips like pocket PB1 and PB2	Mutation in PBD trp414-phe disrupts the PLK-1 subcellular localization to spindle poles and abolish the function	ND	Lys540, His538, Trp 414; PDB ID: 1 umw	[55, 60, 61, 74]
LLCSpTPNG and LLCSTPNG; Cdc25C-P & Cdc25C	Optimal phosphopeptide; derived from Cdc25C protein	NA	Kd = 1.8 µM	LLCSpTPNG is recognized by the trp414 residue of PB1	The loss of function study showed that trp414-phe diminished the molecular recognition and subcellular localization of PLK-1 to the centrosome	ND	Trp414; PDB ID: 2ojs, 2ogq	[75]
PLHSpT	Minimal phosphopeptide; derived from PBIP1 protein for p-T78 motif	NA	Kd = 0.445 µM	The side-chain of N-terminal Pro docked into a surrounding core of hydrophobic amino acid Trp414, Phe535, Arg516 residue	PLHs-Pmab leads the mitotic arrest I HeLa by the inhibition of PLK-1-PBD	ND	His538, Lys540, Trp414, Phe535, Arg 516; PDB ID: 3hik	[41, 76]

a = PLK-1, b = PLK-2, c = PLK-3, d = PLK-4, ND = not determined, PLK = polo-like kinase, IC₅₀ = half-maximal inhibitory concentration, EC₅₀ = effector concentration for half-maximum response, BTK = Bruton’s tyrosine kinase, FHA = forkhead-associated domain, GST = glutathione-S-transferase; LCK = lymphocyte-specific protein tyrosine kinase, PBD = Polo box domain, PIN1 = peptidylprolyl cis/trans isomerase, Plx1 = Xenopus homologue of PLK-1, SH2 = Src homology 2, STAT = signal transducer and activator of transcription, CDC25C = M-phase inducer phosphatase 3, Chk-2 = checkpoint kinase-2, NA = not available.