PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

Table 1

PLK-1 kinase domain-targeted inhibitors.

Compounds	Chemical class	Synonyms	IC50 values for PLK-1^a	Mechanism of action	Selectivity	Selectivity index; = b/a, = c/a, = d/a	Interacting residues	References
BI 2536	A dihydropteridinone developed by; Boehringer Ingelheim	UNII-4LJG22T9C6, BI-2536	0.83 nM	ATP-competitive inhibitor	(i) Exhibited 1,000-fold selectivity against a wide panel of tyrosine and serine/threonine; kinases; (ii) PLK2^b IC50 = 3.5 nM; (iii) PLK3^c IC50 = 9.0 nM; (iv) EC50 = 2–25 nM	-fold; -fold; = ND	Cys133, Leu132, Leu59, Arg136, Arg57, Glu140, Cys67, Lys82, Ala80, Leu130, Gly60, Phe183, Asp194, Val114 PDB ID: 2rku (hPlk1 KD 13–345, T210V)	[11, 16, 31, 64]
BI 6727	A dihydropteridinone; developed by; Boehringer Ingelheim	Volasertib (USAN), UNII-6EM57086EA	0.87 nM	ATP-competitive; inhibitor	(i) No inhibitory activity against a wide panel of more than 50 protein kinases; (ii) PLK2 IC50 = 5 nM; (iii) PLK3 IC50 = 56 nM; (iv) EC50 = 11–37 nM	-fold; -fold; -ND	Cys133 (hPlk1 Kinase domain 13–345, T210V); PDB ID: 3fc2	[34, 65]
GSK 461364A	Thiophene benzimidazole; developed by; Glaxo SmithKline	UNII-8QO27TK6Q4,; GSK-461364,; 2-Thiophenecarboxamide, 5-(6-((4-methyl-1-piperazinyl)methyl)-1H-benzimidazol-1-yl)-3-((1R)-1-(2-(trifluoromethyl)phenyl)ethoxy)-	2 nM	ATP-competitive; Inhibitor,	Has 400-fold greater; potency for PLK1 than for PLK2 and PLK3, EC50 < 50 nM in > 83% of the 120 cancer cell lines tested	and -fold; = ND	Glu140 (Homology; Model)	[24–27, 66]
ON01910.Na	Undefined by; Onconova Therapeutics	Rigosertib sodium’Novanex, UNII-406FL5G00V, Estybon	9-10 nM,	A non-ATP-competitive Plk1inhibitor; Affects microtubule; dynamics	Also inhibits PDGFR, ABL, FLT1, CDK-2, PLK-2, Src, and Fyn. Efficacious both as a single agent and in combination with cytotoxic drugs in xenograft models	ND	ND	[11, 14, 15, 67]
HMN-176	Stilbazole compound by Nippon Shinyaku; Co. Ltd.	(E)-4-((2-N-(4-Methoxybenzenesulfonyl)amino) stilbazole)1-oxide	118 nM	ATP-competitive inhibitor	Shows potent antitumor activity in gastric, breast, and lung human tumor xenografts and so forth.; Better activity compared to known drugs such as cisplatin, doxorubicin,; vincristine, and tegafur-uracil; Inhibits the expression of NF-Y and induces the cell cycle arrest	ND	ND	[19, 21, 22]
Cyclapolin 1	Benzthiazole-3-oxide derivative developed by Cyclacel Ltd., Cambridge, UK	Calthor, Citosarin, Cyclapen, Noblicil, Orfilina, Ultracillin, Cyclapen-W, Vastcillin,Vipicil,Wypicil Ciclacillinum, Cyc-800	20 nM	Noncompetitive; with respect to; ATP	Inhibits PLK1; other family members were not determined; Inhibits C-terminal Src kinase; IC50~100 µM; Cell cycle may also be affected; in G1/S	ND	ND	[42]
DAP-81	Diaminopyrimidine; Derivative by R0ckefeller University, New York	Dialkylphthalate-810,; DAP-810	0.9 nM	Predicted to target the nucleotide; pocket	Destabilized kinetochore; microtubules.; Dose-dependent reduction of CDC25C phosphorylation in cells and recapitulation of key aspects of the loss-of-function phenotype for PLK1	ND	ND	[43]
NMS-P937	Pyrazolequinazoline; by Nerviano; Medical Science	UNII-67RM91WDHQ; NMS-1286937	20 nM	ATP-competitive; inhibitor	More than 100 cell lines and 200 protein kinases have been tested; Shows prolonged M phase and induce apoptosis; Active in Xenograft tumor model; IC50 < 100 nm on solid tumor	ND	Giu131, Cyc133, Lys82, Asp194, Cys67, Phe183, Arg57, Leu132-Cys133-Arg134	[20, 23, 29]
ZK-Thiazolidinone	Developed by Bayer Schering Pharma AG, Berlin, Germany	TAL	19 ± 12 nM	ATP-competitive; Inhibitor	Induced arrest in; prometaphase-like arrest and finally cytokinesis failure and multinucleation IC50 = 0.2–1.3 μM on human and mouse tumor cell lines	ND	ND	[44]
PHA-680626	Pyrrolo-pyrazole derivative	NA	0.53 nM	ND	PLK-2 (IC50 = 0.07 µM) PLK-3 (IC50 = 1.61 µM) Weaker inhibition was detected on few kinases	-fold; = more than 3000-fold	Glu131, Cys133,; Lys82, His105; PDB ID: 2owb; (hPlk1 KD, T210V)	[15]
SBE13	Vanillin derivative	NA	EC50 = 12–39 µM	ND	Shows 1000-fold selectivity within the PLK family	or or -fold	Arg93, Asp194, Cys133, Phe195, Phe183; (By homology model)	[45]
LFM-A13	α-cyano-β-hydroxy-β-methyl-; N-(2,5-dibromophenyl)-propenamide	NA	Plx1 32.5 µM; using GST-CDC25; as a substrate		PLK-3 IC50 = 61 µM; Also inhibits human BTK with an IC50 of 17.2 ± 0.81 µM; The activity is 3–15 fold greater against a panel of protein kinases	ND	ND	[47, 48, 68]
Scytonemin	Subunit derived from; tryptophan and; Phenylpropanoid isolated from many strains of cyanobacteria.	(3,3′-Bis((4-hydroxyphenyl)methylene)-(1,1′-bicyclopent(b)indole)-2,2′(3H,3′H)-dione)	2.0 ± 1 µM	ATP-competitive; Inhibitor	Also inhibits the transcriptional factor MYT1 CDK-1, Chk-1, and PKC; Does not directly inhibit PLK-1 up to 3-4 µM	ND	ND	[7, 12]
Wortmannin	Steroidal furanoids,; originally isolated from Penicillium wortmannii	BRN 0067676,; NSC 627609,; SL-2052,; UNII-XVA4O219QW,; Wartmannin	24 nM	ATP-competitive; Inhibitor	Also inhibits the other member of PLK family and interacts with similar binding affinity; Inhibits the PI3K	ND	Lys68 Cys119; PDB ID: 3d5x; (zebrafish Plk1 kinase domain, 1–312 wild type; and 13–312 T196D)	[13, 17, 18]
RO3280	Pyrimidodiazepines derivatives	NA	0.09 nM	ATP-competitive; Inhibitor	318 wild type and mutants protein kinases tested; More than 85% protein kinases inhibits at 1 mM	500- greater binding affinity with PLK-1 compared to tested penal of protein kinases	ND	[49]
TAK-960	[4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9 tetrahydro-5H pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide]	TAK 960,	0.8 nM	ATP-competitive; Inhibitor	No inhibitory activity against 282 protein kinases; Anti-tumor activity against TP53, KRAS, MDR mutated cell lines; Monopolar spindle and G2/M phase arrest	-fold; -fold; = ND	ND	[53]
Compound 36	Imidazopyridine derivative	NA	9.8 nM	ATP-competitive; Inhibitor	No inhibitory activity against 212 protein kinases at 1 µM.; Tolerated toxicity observed against WBC	-fold; -fold; = ND	Cyc133, Lys82, Asp194	[27, 46]
Compound 15	2-Amino-isoxazopyridine	NA	0.051 µM	ATP-competitive; Inhibitor	Treated cells showed monopolar phenotype and mitotic arrest in colorectal carcinoma cell lines	-fold; -fold; = ND	ND	[51]
Compound 38	Derivative of 2-amino-pyrazolopyridines	NA	0.042 µM	ATP-competitive; Inhibitor	HCT116 colorectal cancer cell lines showed G2/M arrest and induced apoptosis	and -fold; = ND	Phe169, Cys53,; Cys119, Lys68; (hPlk1Lys82), Asp180; (hPlk1Asp 194),; PDB ID: 3dbc; (zPlk1KD, T196D)	[52]
TKM-080301 RNAi	Lipid nanoparticle based formulation developed by Tekmira Phaarmaceuticals Corp.	NA	ND	Silencing PLK-1 mRNA	Showed antiproliferative and gene silencing activity against human cancer cell lines; Antitumor activity against human cancer xenografts	ND	PLK-1 mRNA silencing	[69]

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, PBD = Polo box domain, NIMA-interacting 1, Plx1 = Xenopus homologue of PLK-1, MYT1 = myelin transcription factor 1, PDGFR = platelets derived growth factor receptor, ABL = Abelson murine leukemia viral oncogene homolog 1, FLT1 = vascular endothelial growth factor receptor 1, CDK-1/2 = cyclin-dependent kinase-1/2, PKC = protein kinase C, PI3K = phosphoinositide-3-kinase, KRAS = Kirsten rat sarcoma viral oncogene homolog, TP53 = tumor suppressor p53, NF-Y = nuclear transcription factor Y subunit alpha, CDC25C = M-phase inducer phosphatase 3, Chk-1 = checkpoint kinase-1, and NA = Not available.